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:
Most recently, in as-yet-unpublished work, Dr.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:
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 ....
-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]
