[tt] methuselahfoundation: progress report december 2007

[Alejandro Dubrovsky]

(
http://blog.methuselahfoundation.org/2007/12/methuselah_foundation_newslett_1.html
)

Methuselah Foundation Newsletter and Progress Report, December 2007

Welcome to the first issue of the Methuselah Foundation's newsletter! We
will be sending out this newsletter each quarter to keep you, our valued
donors and supporters, up to date with solid progress in the
Foundation's efforts to advance the engineered reversal of the molecular
and cellular damage of aging - and also of the complementary efforts of
scientists from all over the world.

Donations Tripled Until End of 2007!

Thanks to the challenge pledges made by PayPal co-founder Peter Thiel
and 300 Member Michael Cooper, donations to SENS research are currently
tripled in value - but only until the end of 2007. If you've been
considering making a donation, now is the time!

All donors giving at least $100 are also eligible to receive a free,
signed copy of Ending Aging, Dr. de Grey and Michael Rae's recent book
on rejuvenation science.

SENS3: A World-Class Success

September 2007 saw the third SENS conference in Cambridge, England,
which once again featured world-class research from an outstanding panel
of scientists. The SENS conference series, although new, is now firmly
established as the most exciting in the field, and the pace of discovery
is already increasing.

Videos of the sessions are now available at the Foundation's website,
alongside material from previous SENS conferences and the Edmonton Aging
Symposium, organised by Foundation volunteer Kevin Perrott.

Upgrading the Methuselah Foundation Website

If you haven't visited www.methuselahfoundation.org recently, you may be
surprised to see how much has changed - we welcome feedback and
suggestions on our new look and features. Among many other additions we
now have an integrated Amazon store, all purchases from which help to
support the Foundation.

In This Issue

We are currently sponsoring research in two of the seven strands of the
SENS program; the preventing the harm caused by mitochondrial mutations
(MitoSENS) and degrading damaging long-lived cellular debris (LysoSENS).
Although this work began only recently, our teams have already seen
interesting results and are moving forward rapidly. Their work is
detailed in the Progress Report section of the newsletter, accompanied
by highlights of related work from other groups.

Next, Michael Rae presents a selection of key advances in areas
important to SENS, accomplished by laboratories outside the Foundation.
Dr. de Grey then describes a selection of prospective projects for which
the Foundation is now actively marshalling funds.

Finally, Elliot Bergman provides us with an update on the Foundation's
first funding program, the Mprize, whose total value is now well over $4
million.

Contents

 * Progress Report
 * MitoSENS - Mark Hamalainen
 * MitoSENS: Several Promising Approaches - Michael Rae
 * LysoSENS - John Schloendorn
 * LysoSENS: Tackling Tau - Michael Rae
 * SENS Around The World - Michael Rae
 * Current Goals - Aubrey de Grey
 * Mprize Status - Elliot Bergman

We hope you enjoy the newsletter, and welcome any comments or
suggestions for the March issue!

- Newsletter Editor: Ben Zealley (ben at sens.org)

Progress Report

MitoSENS
Mark Hamalainen
Cambridge University / Quinze-Vingts National Center of Ophthalmology,
Paris

The ultimate goal of MitoSENS is to transfer all 13 human mitochondrial
protein-encoding genes from their present home in the mitochondria to
the protected cell nucleus. This would represent a panacea for
mitochondrial DNA related disease, including the gradual loss of
mitochondrial function that occurs during aging, by allowing the genes
to function in the nucleus even when damaged or destroyed in the
mitochondria.

Plenty of examples exist in nature: intracellular gene transfer from the
mitochondrial DNA to the nucleus has occurred throughout the evolution
of eukaryotes. Some mitochondrial genes, such as subunit a (A6) of ATP
synthase are rarely found in the nucleus, however. One exception is
found in the algae, Chlamydomonas reinhardtii, which in evolutionary
terms has only recently transferred the A6 gene to its nucleus.

In practice, the transfer of mitochondrial genes to the human nucleus
(to produce what is called allotopic expression of the genes) has proved
to be anything but straightforward. We've recently found that targeting
messenger RNA (mRNA) to ribosomes proximal to mitochondria may be
critical to achieving successful allotopic expression. Fibroblasts
carrying the NARP or LHON mutations were rescued by this strategy,
demonstrated by restoration of their ability to grow in galactose media.
Experiments in 143B osteosarcoma cells have failed to replicate this
result. However, it is possible that cancer derived cell lines are poor
models for studying allotopic expression as mitochondrial dysfunction is
thought to be important in carcinogenesis.

Our current primary goal is to explore methods for reducing the toxic
side effects of allotopic expression, by reducing protein hydrophobicity
and reducing or regulating expression levels. Plasmids have been
constructed containing a nuclear version of A6, each including up to
seventeen naturally occurring polymorphisms that reduce hydrophobicity.
A plasmid containing the human CF6 promoter, which drives expression of
a mitochondrial protein associated with Complex V of the respiratory
chain, has been constructed and is being tested.

The ability of these methods to eliminate toxicity will be tested by
expressing the constructs in cells that can be differentiated into a
non-dividing state. The second objective of our work is to achieve
co-expression of multiple mitochondrial genes with the eventual goal of
complementing rho zero cells (which lack any mitochondrial DNA at all).

Further Reading

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

MitoSENS - Several Promising Approaches
Michael Rae
Research Assistant to Dr. de Grey

Excitingly, work on allotopic expression and related "engineering"
solutions to mitochondrial mutations is also taking place in other labs
around the world, using a variety of different biotechnological
approaches. Several groups reported their progress in these areas at the
third SENS conference.

Dr. Marisol Corral-Debrinski, of Paris' Quinze-Vingts National Center of
Ophthalmology, presented her latest results in optimizing the import of
allotopically-expressed mitochondrial proteins by shifting their
production site closer to the mitochondria themselves. This technique is
hoped to overcome a primary challenge in allotopic expression: how do
the proteins now produced by nuclear DNA get back to the mitochondria
where they are needed? She used this technique to insert an allotopic
version of the defective human gene that causes the mitochondrial
disease Leber's Hereditary Optic Neuropathy (LHON) into mouse retinas,
reproducing the same cell loss and abnormal lack of cell communications
branching that appears in the disease. She next hopes to take this to
the next level, and cure the disease in mice by introducing the healthy
gene.

Another way to ease the import of twisted-up (and thus hard to import
back into mitochondria) allotopically-expressed proteins is through the
introduction of special 'bracing bars' called inteins into them, to hold
apart their snarling bends and kinks - an idea first proposed by Dr. de
Grey in a 2000 paper in Trends in Biotechnology. After some preliminary
work done by Japanese scientists, the University of Zaragoza's Dr.
Antonio Enriquez has now picked up the ball, and described his early
work with mitochondrial protein inteins during the meeting.

In addition to the work on allotopic expression, two presentations at
SENS3 covered progress on entirely novel ways of overcoming the problem
of mitochondrial mutations. Dr. Volkmar Weissig of Northeastern
University reported the import of whole new mitochondria into the cell,
an effect that had actually previously been reported by Jerry Shay's
group in 1982 - and then forgotten! - but which Dr. Enriquez was able to
confirm in his own lab.

Finally, Dr. Samit Adhya of the Division of Molecular and Human Genetics
at the Indian Institute of Chemical Biology is pursuing yet another
innovative approach, in which he proposes to dispense with the need for
mitochondrial DNA altogether, by instead providing the mitochondrial
protein-making machinery directly with the "working
instructions" (messenger RNA) that it normally receives in the form of a
transcribed copy of the mitochondrial DNA.

Dr. Adhya's work borrows a trick used by a single-celled organism called
Leishmania tropica to move messenger RNA into the mitochondria. He
provided evidence that RNA imported into the mitochondria of human cells
using this technique works as it should by introducing antisense RNA -
RNA that is designed as a mirror-matched copy of the original, to which
it binds and which it thereby inactivates. Introducing this antisense
RNA exerted effects similar to those seen in people with defective
copies of the genes that he had effectively kept from functioning as
sources of mitochondrial proteins, supporting their functionality as
silencing RNA.

As with Dr. Corral-Debrinski's work, the next step will be to introduce
functional RNA into animal models with dysfunctional mitochondrial
genes, to see if it can restore normal function.

Further Reading

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

J.A. Enriquez. "Inteins and allotopic expression of mtDNA encoded
proteins"
Rejuvenation Res. 2007 Sep;10(Suppl1):S28(Abs 36).

V. Weissig, E. Katrangi, S.V. Boddapati, G.G.M. D'Souza. "Manipulating
(rejuvenating?) the mitochondrial genome"
Rejuvenation Res. 2007 Sep;10(Suppl1):S50(Abs 124).

S. Mukherjee, B. Mahata, B. Mahato, S. Adhya. "Use of a parasite-derived
protein complex to modulate the function of mitochondria in human
cells."
Rejuvenation Res. 2007 Sep;10(Suppl1):S19(Abs 2)

LysoSENS
John Schloendorn
Biodesign Institute, Arizona State University

As we age, our bodies produce many types of junk molecules as a
side-effect of normal functioning. For some of these molecules, no
efficient removal system exists, and their accumulation gives rise to
deposits of intracellular junk. This leads to age-related storage
disease. The major diseases of this type are Alzheimer's disease
(beta-amyloid plaques in the brain) atherosclerosis
(7-ketocholesterol/7KC, a cholesterol derivative in the artery wall),
age-related macular degeneration (a compound called A2E in the eye), and
diabetes (AGEs, sugar-derived protein-modifications, throughout the
body). Medical Bioremediation is the field of research seeking
environmental microorganisms that break these molecules down, whose gene
products can then be harnessed for therapy in humans.

For the past two and a half years, the Methuselah Foundation has been
funding research into Medical Bioremediation at Arizona State's
Biodesign Institute in Tempe, Arizona and at Rice University, Austin,
Texas. When these projects began in the summer of 2005, there was no
strong evidence to suggest that any enzymes or organisms degrading
intracellular junk existed in nature. But this did not intimidate
Methuselah Foundation research volunteers Jacques Mathieu, Mark
Hamalainen and John Schloendorn. With very limited funding and
compensation, they visited leading environmental resarchers Pedro
Alvarez, PhD and Bruce Rittmann, PhD at their labs and began culturing
experiments. All three reseach volunteers had successfully cultured 7KC
degraders before the end of 2005.

This initial success laid the foundation for the scaling-up and
professionalization of these projects. In 2006, Mathieu and Schloendorn
enrolled as PhD candidates at their universities and won departmental
support. Hamalainen has now enrolled at University in Paris, France to
pioneer Mito-SENS as a second Methuselah-Foundation funded effort.

2006 saw further characterization of the 7KC degraders and corroboration
of the results. In summer 2007, six undergraduate research assistants
and one additional PhD candidate joined the effort at Biodesign
Institute. They helped with synthesizing additional target compunds,
such as A2E and CML (a major AGE). This veritable army of volunteers
also was able to culture six independent degraders of CML, and identify
two enzymes which break A2E in different ways.

Today, researchers at the Biodesign lab are working on identifying the
enzyme initiating the breakdown of 7KC and CML. They are also
characterizing the A2E-degrading enzymes further, and are preparing to
move them into a cell model of age-related macular degeneration for
initial safety and efficacy testing. Various other projects at the Tempe
lab are at earlier stages. Novel targets include artificial lipofuscin
and the infamous glucosepane AGE-crosslink.

Meanwhile, Mathieu at Rice University employs a modern microarray-based
approach to identify genes that get expressed in the presence of 7KC,
but not other nutrients. Such enzymes are likely involved in the
breakdown of 7KC. This has the potential to characterize the complete
genetics of 7KC degradation in one elegant experiment.

Further Reading

Rittmann BE, Schloendorn J. "Engineering away lysosomal junk: medical
bioremediation."
Rejuvenation Res. 2007 Sep;10(3):359-65.

LysoSENS - Tackling Tau
Michael Rae
Research Assistant to Dr. de Grey

Neurofibrillary tangles (NFTs), aggregates of the protein tau, are a
kind of molecular damage that accumulates inside our brain and other
nerve cells with aging, and are associated with Alzheimer's and a
variety of rare neurological diseases. There's good reason to think that
removing these tangles would help to rejuvenate the aging brain. The
cell already has an 'incineration and recycling center', the lysosome,
which is responsible for the removal of damaged molecules within itself,
so the age-related accumulation of NFTs in brain cells suggests some
essential weakness in lysosomal functioning - either a failure to engulf
NFTs, or a lack of the enzymes needed to shred them up into reusable
parts once they have been taken in.

This summer, scientists working in the New York University School of
Medicine under Dr. Einar Sigurdsson reported that the burden of NFTs
could be significantly reduced, and neurological function substantially
preserved, in laboratory animals that normally suffer neurological
damage because of a genetic predisposition to form NFTs, by immunizing
them with a form of the tangles' precursors. This appeared to result
from the antibodies' shepherding the NFTs into the lysosome for
disposal. The benefits were mild, but could likely be enhanced by
fortifying the lysosome with enzymes more suited to recycling the NFTs -
a projected project for the LysoSENS strand of the SENS platform.

Further Reading

Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. "Immunotherapy
targeting pathological tau conformers in a tangle mouse model reduces
brain pathology with associated functional improvements."
J Neurosci. 2007 Aug 22;27(34):9115-29.

SENS Around The World
Michael Rae
Research Assistant to Dr. de Grey

Toxic Cells

In January, Dr. Alan Saltiel and his colleagues at the Departments of
Internal Medicine and Physiology at the University of Michigan Medical
School reported results that will be central to the implementation of
one of the SENS platform's planks: the removal of one of the several
classes of toxic cells that accumulate in the body over time. We've
known for some time that the systemic inflammation, insulin resistance,
increased levels of blood fats, and other metabolic disorders that
progress with aging is mostly related to the accumulation of body fat
over the lifespan. Recently, however, we've come to understand that the
metabolic effects of being overweight are not the result of having more
fat generally, but are due to the attraction of inflammatory immune
cells into the so-called "visceral" body fat (the depot around the
internal organs of the gut).

The removal of these cells would thus reverse the metabolic dysfunction
that they induce, restoring a more youthful systemic metabolism. But to
do that requires a way of selectively targeting such cells, while
leaving healthy immune and fat cells alone.

Dr. Saltiel's lab has now reported that these immune cells have
distinctive binding sites and sugar-protein markers that distinguish
them from their beneficial cousins elsewhere in the body. This will
allow us to develop interventions similar to vaccines and some of
today's targeted cancer therapies, removing the toxic cells with minimal
collateral damage.

Further Reading
Lumeng CN, Bodzin JL, Saltiel AR. "Obesity induces a phenotypic switch
in adipose tissue macrophage polarization."
J Clin Invest. 2007 Jan;117(1):175-84.

Current Goals
Aubrey de Grey
Methuselah Foundation

A selection of projects within the SENS plan are ready to be launched as
Foundation-sponsored research programs, conditional only on the
availability of sufficient funding. As for MitoSENS and LysoSENS, these
projects will start small (likely with only a single researcher), with
the aim of delivering high leverage in terms of the credibility of the
approach.

Amyloid in tissues other than the brain

Most people are aware of the amyloid deposits associated with
Alzheimer's Disease: they are the main constituent of senile plaques,
the aggregates that accumulate in the spaces between neurons as the
disease progresses. Encouraging progress is being made in stimulating
the body's immune system to eliminate these deposits. However, amyloid
composed of different proteins also accumulates in other tissues during
aging. Progress in removing these other amyloids has been much less
intensive thus far, even though they are, if anything, more clearly
linked to the progression of age-related illness than senile plaques are
to Alzheimer's. I have been in preliminary discussion with one of the
leaders in this area, with a view to initiating work as soon as
possible.

Identifying genes essential for ALT

WILT, the anti-cancer therapy incorporated into SENS, entails (among
other things) the elimination of genes for the enzyme telomerase, which
allows cancer cells to divide indefinitely without losing material from
the ends of their chromosomes. Unfortunately, about 10% of cancers solve
this problem in a different way, not using telomerase, via a process
known as ALT, for alternative lengthening of telomeres. Even more
unfortunately, ALT is still only very poorly understood. Recently,
however, some intriguing observations in two different organs have given
good reason to suspect a hitherto unsuspected gene. A relatively simple
sequence of initial experiments could test this, and I am already in
discussions with a leading ALT researcher concerning the possibility of
launching this project.

Mprize Status and Future Prospects
Elliot Bergman
Mprize Competitor Coordinator

The Mprize is designed to jumpstart scientific research into
life-extending biomedicine with the twin incentives of (1) a large cash
award, and (2) a prestigious public victory in a prominent research
competition. The support of our generous donors is the key to this
strategy: the magnetic draw of the Prize grows with every dollar pledged
to this program. Therefore, we are pleased to report a substantial
increase in the total amount of money in the Mprize fund, which now
stands at $4.6 million.

To broaden the field of competing research, a focused program was
initiated this year to actively recruit new competitors, expanding the
"mouse race" for breakthroughs in preventive and regenerative anti-aging
biotechnology. Spearheading this campaign is Elliot Bergman, Ph.D., of
biotech consulting firm ChemLifeSciences, as the Foundation's Competitor
Development Coordinator.

Elliot's efforts to date have brought in four new competitors for the
Prize, for a total of eleven scientific teams independently racing to
extend the lives of their furry subjects as of this writing. The four
most recent additions are Professor Andrzej Bartke of Southern Illinois
University; Professor Craig Cooney of the University of Arkansas for
Medical Sciences; Alan Cash, founder of Terra Biological LLC; and Elise
Sacane, co-founder of Neural Learning Systems. Each of these teams is
testing a different anti-aging strategy, creating exactly the kind of
wide-open, multi-strategy competition needed to weed out ineffective
approaches and bring successful therapies into the spotlight.

Several other potential competitors have been identified and are being
qualified for participation. We hope to have a total of 13-15
competitors by the first quarter of 2008.

We are particularly delighted that Professor Andrzej Bartke a renowned,
world-class gerontologist has now announced that he will re-enter the
fray in a second round of competition. In 2004, his Growth Hormone
Receptor Gene Knockout (GHR-KO 11C) mice set the standard against which
future competitors for the preventive ("Longevity") Prize will be
judged: a previously unheard-of lifespan of 1819 days, or nearly five
years - a remarkable 50% extension of lifespan compared to normal,
healthy mice. Dr. Bartke has not yet disclosed the new protocol that he
will be testing in this second season of the anti-aging challenge, but
we can be certain that he will be a major factor in the race.

In addition to putting his own mice onto the gridiron, Professor Bartke
is now also leading the Foundation's efforts to promote the wider use of
mice as an experimental model for anti-aging research. Today, the trend
is increasingly toward studies in cheaper, shorter-lived organisms such
as roundworms, yeast, and fruit flies - organisms that are progressively
poorer proxies for human test subjects with every evolutionary step that
they take away from us. Success in this initiative would not only
attract many more new competitors to the Prize, but also broaden the
range of interventions being tested within and without the Prize
structure. We aim to enhance the impact of mouse research in general,
and to the Methuselah Foundation in particular, while increasing the
yield of results that are likely translatable into human interventions.

We have also secured access, through cooperation with the National
Institute on Aging (NIA) division of the National Institutes of Health
(NIH), to a database of US-government-funded projects on mouse aging
research, invaluable as a source of potential new competitors. It is
notable that 3 of our 4 new competitors are supported, at least in part,
by NIA/NIH grants, while two are scientific entrepreneurs who have
raised private capital to fund part (Cash) or all (Sacane) of their
Mprize research. We are scouring other external sources - such as
reports in the scientific literature, and grant applications submitted
to other non-governmental scientific organizations such as the Ellison
Medical Foundation for additional potential competitors. In addition we
follow up with researchers testing new aging treatments in rats, or in
cultured cells or tissues, in an effort to identify new approaches which
should result in lifespan studies in mice.

Future prospects for the Mprize look bright, although there are some
important challenges that continue to discourage use of mice as test
subjects for anti-aging interventions. A major limiting issue is the
relatively high cost of this research, which can range into the hundreds
of thousands of dollars per year, as well as the length of time required
to complete lifespan studies in an animal that normally lives for over
three years. A hopeful sign is that despite these disincentives, several
well-funded start-up companies in the new, important Nutritional
Genomics field - such as Sirtris and IKARIA - are recognizing the
importance of testing their interventions in mammals, and will likely be
using mice extensively in their research.

We are assessing the possibility of reducing research costs by
outsourcing mouse trials to well-organized laboratories in Asia (mainly
China, India, Japan, Thailand, and South Korea), where strict scientific
standards can be assured. If such an international research facility
becomes available, the scale of the investment required to perform mouse
studies will be reduced considerably, broadening the scope of mouse
treatments that can be tested and allowing a wider variety of new
competitors to take up the gauntlet.

Another way of limiting the cost and time required to perform anti-aging
studies in mice is to encourage more researchers to compete in the
Rejuvenation arm of the Mprize, which requires researchers to test their
interventions in 16-month-old mice (instead of starting at weaning, as
in the Longevity prize). Most of the Foundation's donors already favor
the Rejuvenation Prize over the Longevity Prize by a very large margin,
as measured in completed pledges to the two Prize funds: $1.48 million
vs. $0.16 million - a ratio of more than 9 to 1. This preference is
based on the urgent need to develop interventions that can extend the
healthy life spans of people who are already middle-aged, in hopes that
people alive today can still be rescued from a death by biological decay
brought on by the aging process.

Posted by Reason on December 14, 2007 11:09 PM