Next Steps For Longevity Science at the Methuselah Foundation
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As you might know, Aubrey de Grey's Strategies for Engineered Negligible Senescence (SENS) places the known forms of biochemical damage that cause aging into seven categories, each with a recommended path towards repair or prevention:

1) Too few cells: Some tissues lose cells with advancing age, like the heart and areas of the brain. Stem cell research and regenerative medicine are already providing very promising answers to degeneration through cell loss.

2) Cancer: We must eliminate the telomere-related mechanisms that lead to cancer. de Grey suggests selectively modifying our telomere elongation genes by tissue type using targeted gene therapies.

3) Mitochondrial damage: Mitochondrial DNA is outside the cellular nucleus and accumulates damage with age that impairs its critical functions. de Grey suggests using gene therapy to copy mitochondrial DNA into the cellular nucleus. Other strategies for manipulating and repairing damaged mitochondrial DNA in situ were demonstrated for the first time in 2005.

4) Molecules gummed together with crosslinks: Some of the proteins outside our cells, such as those vital to artery walls and skin elasticity, are created early in our life and never recycled or recycled very slowly. These long-lived proteins are susceptible to chemical reactions that degrade their effectiveness. Scientists can search for suitable enzymes or compounds to break down problem proteins that the body cannot handle.

5) Too many cells: Certain classes of senescent cell accumulate where they are not wanted, such as in the joints. We could in principle use immune therapies to tailor our immune systems to destroy cells as they become senescent and thus prevent any related problems.

6) Junk between the cells: As we age, junk material known as amyloid accumulates outside cells. Immune therapies (vaccines) are currently under development for Alzheimer's, a condition featuring prominent amyloid plaques, and similar efforts could be applied to other classes of extracellular junk material.

7) Junk inside the cells: Junk material builds up within non-dividing, long-life span cells, impairing functions and causing damage. The biochemistry of this junk is fairly well understood; the problem lies in developing a therapy to break down the unwanted material. de Grey suggests searching for suitable non-toxic microbial enzymes in soil bacteria that could be safely introduced into human cells.

The Methuselah Foundation has modestly funded work on items #2 and #7 above since 2006, whilst research fundraising was in the early stages, as MitoSENS and LysoSENS:

The most promising approach [for LysoSENS], in my view, is to enable cells to break the junk down so that they don't fill up after all. This can be accomplished by equipping the lysosome with new enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. This suggests that the micro-organisms present in soil have enzymes capable of breaking these aggregates down, and preliminary work in my old department in Cambridge, as well as work now being carried on at Arizona State University, has already confirmed this optimism.

...

MitoSENS research began at Cambridge University, in the MRC-Dunn Human Nutrition Unit. Ian Holt, Ph.D., head of the Mitochondrial Diseases research at the Dunn - who supervised the first MitoSENS projects - commented, "For over 30 years mutations in mitochondrial DNA have been suspected to be important contributors to aging. If we can incorporate working copies of that mtDNA into our nuclear DNA, the mtDNA will be rendered superfluous and any mutations it suffers will be inconsequential. Researchers have tried to do this for many years, with only limited success. The work that Mark will perform in my lab is the most systematic attempt yet to get this technology to work."

This March 2008, the Methuselah Foundation has transferred its MitoSENS Research program to the lab of Dr. Marisol Corral-Debrinski in the newly opened Institut de la Vision in Paris. Dr. Corral-Debrinski began her career studying mRNA localization to the mitochondria in yeast, a process which she identified as essential for mitochondrial gene therapies. She now heads a lab that is applying the mRNA localization approach to the development of gene therapies for treating inherited mitochondrial diseases. The same approach can, in theory, be used to treat the somatic mutations of mitochondrial DNA that play a definitive role in aging. For this reason, we have chosen to collaborate with her to hasten the development of gene therapies that may obviate mitochondrial DNA mutations.

With growth in philanthropic research funding through to the present day, thanks to many generous donors and the rising profile of the Foundation, these promising research programs are expanding. In addition, looking ahead, we can see the groundwork taking place for Methuselah Foundation-funded programs in the other categories of SENS:

AmyloSENS - cleaning up extracellular junk:

The Methuselah Foundation is presently in discussion with leading researchers in this field with a view to initiating work on a vaccine - similar to that developed by Elan for Alzheimer’s disease - to stimulate the aged body to clear the widespread amyloids (particular of transthyretin) responsible for senile systemic amyloidosis.

ApoptoSENS - removing senescent and other "gone bad" cells:

During 2008, the Methuselah Foundation will launch a project to develop a procedure for clearing aged T cells from the blood of mice, and potentially thereafter in primates. This work will be supervised by one of the top professors in the immunosenescence field.

GlycoSENS - breaking down crosslinks and AGEs:

The Methuselah Foundation is currently planning out a project to engineer enzymes capable of cleaving the ubiquitous glucosepane crosslinks, which may comprise as much as 98% of all the long-lived crosslinks in aged human tissue. This work is still in the early planning stages, but we hope to be able to begin full-time research before the end of 2008.

OncoSENS - alter cells to prevent cancer:

The Methuselah Foundation is planning to launch three projects in the OncoSENS strand during 2008.

The first project aims to characterise the enzyme responsible for [alternative lengthening of telomeres], which is still unknown. Recently, however, observations in two different organs have given good reason to consider a hitherto unsuspected gene. A relatively simple series of experiments could test this hypothesis.

The second project addresses a potential problem with the WILT strategy. It’s possible that telomerase activity per se - independent of telomere length - may have roles in maintaining the health of the stem cells themselves, or of their rarely-dividing neighbours in the so-called "stem cell niche". We are arranging a project to address this question, in the blood of mice, with the world’s leading professor in the area.

Finally, the theory that non-cancer-causing mutations are unlikely to be harmful in a normal lifetime - protagonistic pleiotropy - is not yet widely accepted. We are therefore initiating a rigorous study into the effects of such mutations in mouse brains.

RepleniSENS - replacing lost cells:

We need more work in all these areas, even though they are all progressing very encouragingly. However, the current fashion for stem cell research in the international scientific community means that the Methuselah Foundation does not currently intend to allocate its limited resources to projects in this area.

Stem cell research is a well funded field indeed, moving rapidly. I'd wager that the most important technologies for the repair of age-related tissue loss will be developed before 2020, if not fully commercialized (given the present state of what it takes to push anything past the FDA). What I'd also like to see by that time is the growth of active, well-funded research communities for the other areas of SENS. I think that this is very likely: even modest early success in SENS research will gather more established research groups to the fold, more independent funding for the science, and accelerate the process of change and progress in the broader aging research community.

Comments

Very good overview, thank you. You reminded me of the three soil samples I sent to LysoSENS last autumn. They got back to me to let me know that all three had enzymes that could degrade some of the 'junk'. I'll see if I can get an update, I'm really curious to know if anything more came out of them or if they were a dead end.

Posted by: Michael G.R. at June 5, 2008 9:59 AM
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