The SENS Foundation’s research strategy is to support a mix of intramural work at our Research Center and extramural projects at university laboratories elsewhere.
The Research Center has hired five additional full-time and one part-time staff,
including Tanya Jones, our Director of Research Operations. They have two
vibrant projects, within the LysoSENS and MitoSENS project areas.
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LysoSENS team (3 staff) is pursuing enzymatic solutions to the problem of eliminating two of the most notable components of age-related “molecular aggregates” – A2E and 7-ketocholesterol (7KC). A2E is a major cause of dysfunction of retinal epithelial cells, producing age-related macular degeneration (AMD), the leading cause of blindness in the elderly. 7KC, an oxidized derivative of cholesterol, is believed to be a major cause of the degeneration of macrophages into foam cells, which is the first step in atherosclerosis, one of the most lethal age-related diseases worldwide.
The team has developed an in-house process for A2E synthesis, a critical step in
our screening and evaluation programs for A2E-degrading enzymes. One such candidate has been dramatically enhanced by fusion with a second enzyme, accelerating the rate of degradation of A2E up to 100-fold. On the 7KC side, we have identified a number of 7KC-metabolising enzymes, and have successfully subcloned them into a species of yeast which will allow us to determine whether the activity of a particular enzyme will be preserved if expressed in humans. We are developing methods for transfecting these enzymes into macrophages, to determine whether their expression can reverse the foam cell phenotype.
SENS Foundation launched its second major in-house project in the MitoSENS strand, hiring Dr. Matthew O’Connor as research leader in September 2010, and more recently adding Dr. Gayathri Swaminathan to the team. Allotopic expression – the addition of mitochondrially-encoded genes to the nucleus, protecting them from oxidative damage – is expected to relieve many aging-related pathologies, including sarcopenia (loss of muscle with age). Allotopic expression has been demonstrated for three of the thirteen genes required to complete the process in humans: our former collaborators – the group of Dr. Marisol Corral-Debrinski – were responsible for much of this progress. The goal of the new project is to demonstrate allotopic expression of the remaining ten genes, individually and in combination.
In addition to these major projects, a team at the Research Center developed a prototype “scrubber” – a device able to selectively deplete “anergic” (proliferation-resistant) T cells (a type of white blood cell) from the bloodstream of mice. This depletion was demonstrated to result in a long-term return to a more youthful T cell profile, and led to an academic publication and patent. The prototype has since been loaned to our extramural collaborator Dr. Janko Nikolich-Zugich, to conduct further studies.
Supported external research projects
In the lab of Dr. Janko Nikolich-Zugich at Arizona University, we have funded work by Dr. Megan Smithey exploring the relationship between persistent viral infections and immunosenescence, the reduced capacity of the aged immune system to respond to infections. This project has made several exciting discoveries. Most notable is a dramatic improvement in immune response when T cells from young adult mice are transferred into older mice partially depleted of their own T cells, strongly indicating that the decline in function of T cells in aged individuals is due to an intrinsic defect of these cells. The continuation of this work in 2011 is expected to provide sufficient data to allow clinical testing to begin.
In the fall, we initiated two projects: one on removing senescent cells (Kevin Perrott in the lab of Dr. Judith Campisi at the Buck Institute), and one designed in collaboration with the Supercentenarian Research Foundation’s Stan Primmer, involving Drs. Sudhir Paul of the University of Texas and Brian O’Nuallain of Harvard University. This latter project targets senile systemic amyloidosis and isolated atrial amyloidosis. Both are caused by the aggregation of proteins to form damaging amyloids, leading to significant age-related disorders of heart function. The goal is to develop antibodies able to detect and destroy these aggregates.
We continue to fund extramural LysoSENS work by Jacques Mathieu and Rob O’Callahan in the laboratory of Prof. Pedro Alvarez at Rice University. This team has recently produced two enzymes with activity against 7KC, currently being taken forward into cell-based assays. They have also begun development of a selection based assay for mutagenesis libraries – a key step in high-throughput “directed evolution” of the enzymes already discovered.
Also in 2010, SENS Foundation began a multi-project collaboration with the
world-leading Wake Forest Institute for Regenerative Medicine. Projects in the
areas of immunosenescence, extracellular matrix cross-linking, and
intracellular aggregates will start in 2011, conditional on sufficient funding.
At Albert Einstein College of Medicine in New York, SENS Foundation has been funding Dr. Silvia Gravina in the lab of Dr. Jan Vijg, to evaluate whether random changes in DNA methylation (a major type of epimutation) are sufficiently widespread to have a significant impact on the aging process.
The standard protocol for studying these changes involves conditions which typically lead to extensive DNA degradation. This is a particularly serious issue for single-cell analysis, which our work requires in order to detect bona fide adventitious changes, rather than ones made “on purpose” by the cell in response to other types of damage. Dr. Gravina’s first success was in optimizing conditions to minimize such degradation. She was then able to demonstrate that her optimized protocol was effective in single cells of several types – hepatocytes, fibroblasts, and neurons.
A far more reliable assessment of damage can be derived through comprehensive, gene-specific measurements, and Dr. Gravina is now developing this approach using so-called “next-generation” sequencing. Preliminary results are very promising.
An additional requirement for this project is a new method for isolating the target DNA: existing techniques are not effective for neurons, due to their complex and fragile structure. To meet this requirement Dr. Gravina has developed a protocol to enrich single neuronal nuclei.
Drawing together all of these preliminary achievements, Dr. Gravina is now working directly on our project’s ultimate aim – quantifying genome-wide levels of epimutation in the nuclei of single neurons from aged mice – with key results expected in 2011. The interim results are currently being prepared for academic publication in a leading peer-reviewed journal.
SENS Foundation received $1,356,000 of donations in 2010. In addition to expressing our gratitude for all the donations which we received, we would like to thank Peter Thiel, Jason Hope and Dan Stoicescu for their generous support of the Foundation.
Our total expenditure was $1,119,000.
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