SENS Research Foundation is funding with the goal of applying it to a primary problem of aging: the decline of the immune system . Only a few of us will ever need a new portal vein or trachea — but nearly all of us will need a new thymus, which plays an indispensible role in the immune system . The fine structures and functioning cells of the thymus we were born with will slowly degenerate between our teen years and our sixties; as the organ begins to fail with age, we become increasingly vulnerable to influenza and other common infectious diseases. With SRF support, Wake Forest Institute of Regenerative Medicine researchers are now making rapid progress in work to apply the decellularized-recellularized scaffold method to the thymus in animal models . SRF is excited to be spearheading the adaptation of existing techniques to geriatric medicine, where innovation is so sorely needed . But we know that this alone is not enough to address the emerging health crisis posed by agerelated disease, which has surpassed infectious disease as the most pressing health problem facing humanity today
SENS Research Foundation is currently the only research nonprofit pushing the boundaries of the field toward the molecular level, where much of the damage of aging resides. Treating the symptoms of the resulting pathologies can only take us so far, because the body’s repair and maintenance mechanisms continue to deteriorate . SRF’s unique dedication to identifying and alleviating the damage that long precedes pathology serves as the basis for much of our work . Our longest-running project in this vein targets age-related macular degeneration, the leading cause of blindness in people over the age of 65 . Macular degeneration is caused by the accumulation of a toxic byproduct of the visual cycle called A2E, which builds up in the retinal pigment epithelial (RPE) cells responsible for maintaining the light-sensing cells of the eye . We are working to preserve and restore the health of these cells by fortifying them with new, engineered enzymes capable of clearing A2E deposits . In 2012, scientists in our Research Center identified an enzyme (SENS20) that has since demonstrated efficacy in degrading A2E not only in vitro, but in RPE cells administered an A2E “stress test .”
Lysosomes
Cells are equipped with specialized “incinerators” called lysosomes, where they send damaged or unwanted material for destruction . Some cellular wastes, however, are so chemically snarled that even the lysosome is unable to shred them .With no way to eliminate these compounds, the cellular garbage simply builds up over time, progressively interfering with cell function . The disabling of specific cell types by their characteristic waste products drives numerous age-related pathologies.
Mitochondria
With funding from SENS Research Foundation, Professor Marisol Corral-Debrinski developed an innovative system for improved delivery of allotopically-expressed proteins into the mitochondria. SRF-RC scientists are now working to master and refine this system and to extend its application to all thirteen of the proteins encoded by the mitochondrial genome. Our team has produced stable cell lines expressing our improved mitochondrial gene constructs in four lines of cells that were taken from patients suffering from severe diseases caused by inherited mitochondrial mutations. Some of the inherited mitochondrial genetic diseases bear a resemblance to many of the diseases and maladies of aging . For example, mutations in the ND1 gene have been implicated in the development of Parkinson’s disease and Cytochrome B (CYB) mutations can cause muscle fatigue / exercise intolerance in young patients.
In 2013, our two primary goals are to definitively confirm the localization of allotopically-expressed proteins at the inner membrane of mitochondria and to demonstrate that our allotopic expression systems can functionally rescue cells with each of several missing or severely mutated mitochondrial genes . Research efforts will be focused on more in-depth and rigorous biochemical and functional characterization of the mitochondrial energy-production chain following allotopic expression of the five missing or defective proteins in our re-engineered mutant cell lines, showing the assembly of the full chain
Identifying and attacking Alternative Telomerase Lengthening (ALT) Cancer
In 2013, the RC team is working to streamline the novel C-circle assay, bringing the turnaround time closer in line with the rapid assays available for telomerase activity. This will put tests for the two maintenance systems on a similar footing for researchers and would allow more rapid testing of candidate ALT genes . The novel assay could also potentially enable a faster classification of patient cancers into telomerase-exploiting and ALT-exploiting tumors . Knowing whether a given person’s cancer uses one mechanism or the other would allow clinicians to give patients more accurate prognostic information and would facilitate personalized medicine using emerging telomerase-inhibiting therapies and future ALT-inhibiting ones .
The ultimate goal remains to use what we learn about the genetic basis of ALT to develop the first therapies able to shut it down, eradicating ALT-based cancers . Such a therapeutic approach could also be combined with telomerase based strategies to create powerful combination therapies against cancer
Battling Artery Stiffening
Our arteries slowly stiffen with age, in substantial part because of chemical crosslinking of their structural proteins by blood sugar and other fuels in the circulation. Like the crosslinking that causes rubber windshield wipers to become stiff and brittle over time, the crosslinking of arterial proteins with age leaves us with increasingly rigid blood vessels . This ongoing stiffening of the blood vessels makes them progressively less effective at cushioning organs like the kidneys and the brain from the relentless pounding of the pulse, and it also leads to an insidious rise in systolic blood pressure with age . Together, these effects contribute to the slow loss of the ability of the kidneys to filter toxins from our blood with age and a rising risk of disabling stroke and dementia.
In aging and diabetic rats, dogs, and even monkeys, prototype drugs that break crosslinks have been shown to reverse the stiffening of the arteries and the heart, improving arterial health and preventing worse pathology. Unfortunately, these first-generation crosslink drugs proved to be much less effective in humans, most likely because they target a particular form of crosslink that is less common in humans.
To make a better crosslink-breaking therapy, we must target the main crosslink that actually builds up in human tissues such as arteries and skin collagen: a complex chemical shackle called glucosepane . A glucosepane-cleaving drug would allow the proteins of aging arteries to move freely again, returning their flexibility and cushioning capacity to youthful health and functionality. As a result, damage to the kidneys would be prevented and strokes averted.
The Cambridge group has been working on methods of extracting intact crosslinked proteins from the tissues of dogs and marmoset monkeys in order to assay their abundance and to test the effects of potential crosslinkbreaking agents . They have also been working on finding ways to measure glucosepane cleavage — first in the test tube, and then in real animal and human tissues . One conclusion has already emerged from this research: none of the commercially-available monoclonal antibodies against related crosslink molecules are able to cleave glucosepane to any significant degree, and many do not even bind it .Dr . Spiegel’s group has also recently published a report clarifying how the first generation crosslink-breaking drug worked . Both of these findings further emphasize the need for novel crosslink-breaking therapies .
The GlycoSENS collaboration expects to begin publishing the results of this research in peer-reviewed scientific papers in 2013 . These results lay the groundwork for our efforts in developing new anti-crosslink therapies, and may be expected to attract more researchers to enter (or return to) biomedical research on crosslinks and new therapies to remove them.
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Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
Known for identifying cutting edge technologies, he is currently a Co-Founder of a startup and fundraiser for high potential early-stage companies. He is the Head of Research for Allocations for deep technology investments and an Angel Investor at Space Angels.
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