Working to Reverse Age-Related Loss of Elasticity in Tissues

Philanthropist Jason Hope is of late writing a series of posts on SENS, the Strategies for Engineered Negligible Senescence. SENS is both a research program and an initiative for change in medical research: the aim is to produce the applications of biotechnology needed to create actual, real, working rejuvenation treatments. Which is to say forms of medicine that can bring aging under control by repairing the known causes of degeneration, the damage in and between cells that causes age-related disease and ultimately death. A sufficiently good implementation of this suite of repair treatments will prevent the young from becoming old, and restore the old to good health and vigor - but even partial treatments and early prototypes will provide sufficient benefits to merit commercial developments.

This is the vision, and at present the SENS Research Foundation works on making this a reality with a modest yearly budget of a little more than $4 million dollars and a network of allies within the advocacy and life science communities. This involves identifying those areas in which the present efforts are lacking, or the tools are absent, or no-one is making enough of an effort, and stepping in to bridge that gap using some combination of funding and persuasion.

It is sad to say, but - once you look beyond the fields of stem cell and cancer research - gaps are more or less all there is to see. Meaningful progress towards other needed forms of rejuvenation treatment is conspicuous by its absence. In comparison to stem cell research, the initiatives elsewhere in what will one day be a much broader field of regenerative medicine are sparse, a lab here and a lab there dabbling in matters like mitochondrial repair or building AGE-breakers, to pick two examples. This is far from the energetic and well funded research centers needed for a good rate of progress.

Jason Hope put in half a million dollars a few years ago to help get work underway to bridge one of these research gaps, that related to breaking down the cross-links that build up in important tissue structures with age. This form of damage has detrimental results that include a loss of tissue elasticity that contributes to a range of age-related conditions, yet the life science research community is present ill-equipped to work with the most relevant cross-link compounds in any meaningful way. Here Hope discusses some of the ongoing research that he has funded:

Extracellular Matrix Stiffening

The extracellular matrix acts as a sort of scaffolding that provides support and cushioning to the surrounding cells. The extracellular matrix, or ECM, is an interlinking mesh of fibrous proteins and a few other substances that make the matrix both strong and elastic. The extracellular matrix is very resilient and, in a perfect world, changes very little from the time you are born until you die. In this imperfect world inside the human body, however, blood sugar and other substances bathe the proteins and other compounds of the extracellular matrix. This constant exposure causes unhealthy crosslinks to develop between ECM proteins.

This crosslinking limits the flexible, independent movement of the proteins in the extracellular matrix in that area, causing stiffness and a loss of shock absorption. In time, crosslinking in the extracellular matrix causes it to lose its primary function, leading in turn to dysfunction in the cells, tissues and organs it serves.

Breaking these ECM crosslinks reverses the damage and prevents further pathology. Breaking heart and arterial ECM crosslinks, for example, can reverse stiffening in the heart and blood vessels. In 2011, SENS Research Foundation and the Cambridge University Institute of Biotechnology announced the establishment of a new SENS Research Foundation Laboratory at Cambridge. A targeted donation enabled scientists in the Cambridge SENS center and Dr. David Spiegel's Yale lab to investigate various solutions to glucosepane crosslinks.

One of the first challenges to breaking unhealthy ECM crosslinks is to detect their presence. Dr. Spiegel has developed a technique to synthesize glucosepane in a laboratory. Researchers can now use this synthesized glucosepane to develop reagents capable of detecting glucosepane crosslinking. Scientists can then use those reagents as an aide in the development and testing of new glucosepane-breaking drugs.

Progress in this area could also enable the Cambridge group to develop a method to deal with another major obstacle in breaking ECM crosslinks  -  measuring glucosepane cleavage, first in the test tube then in animal and human tissues. Researchers can use this method to determine the effect a candidate drug has on breaking glucosepane crosslinks. In the course of their research, the Cambridge researchers have already concluded that none of the commercially available methods for detecting crosslinks effectively detects glucosepane  -  and they aren't particularly good at detecting other crosslinks, either! In fact, many of the ECM antibodies currently in use do not even bind to crosslinks.

The findings of both Dr. Spiegel's group and the Cambridge group underscore the need for novel crosslink-breaking therapies. The work performed by both groups further our efforts in developing novel anti-crosslink therapies.

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