The Life Extension Advocacy Foundation (LEAF) volunteers caught up with Aubrey de Grey of the SENS Research Foundation at the recent International Longevity and Cryopreservation Summit held in Spain, and hence the publication of the high level view of current progress in SENS rejuvenation research that I’ll point out today. The conference was an opportunity for members the overlapping European communities focused on longevity science, cryonics, and transhumanism to present their work, build their networks, and plan future initiatives. When it comes to longevity, the SENS research program looms large: its focus on repair of the known forms of molecular damage that cause aging so far appears to be the only approach to therapies for aging that can plausibly produce significant rejuvenation in our lifetime. Success here, meaning working rejuvenation therapies in the clinic, is conditional on continued growth in funding and support for this part of the field, however, and while a great deal has been accomplished, there is a lot of work yet to be done.
Over the course of decades, long lived tissues like brain, heart and skeletal muscles gradually lose cells and as replacement dwindles their function becomes compromised. The brain also loses neurons which leads to cognitive decline and dementia as well as the loss of fine muscle movements. The immune system also suffers, with the thymus gradually shrinking and losing the ability to produce immune cells, leaving you vulnerable to diseases. Thankfully stem cell research and cell therapy is already a well advanced field. SENS has not needed to get involved in this area as it is well funded and moving along very rapidly. Only this month we have seen hematopoietic stem cells produced for the first time and research in this field is moving forward at a furious rate. It will be plausible in the near future that we will be able to produce every cell type within the body to replace age related losses.
Cancer uses two pathways to uncontrolled growth: hijacking telomerase and using the Alternative Lengthening of Telomeres (ALT) mechanism. Both allow cancer to maintain its telomeres and grow out of control. Therapies that can inhibit these pathways could be combined and are therefore a potential way for us to defeat all cancers. ALT therapies are progressing following a successful fundraiser on Lifespan.io last year. SENS has been developing a high throughput assay for ALT allowing cost effective candidate evaluation for drugs that can inhibit or destroy cancer cells using ALT. Within the next year a company based on ALT should be possible. Telomerase inhibiting therapies are being developed by a number of organizations and companies so the SENS Research Foundation does not need to get involved with this. Therapies that inhibit telomerase in cancer cells are already in clinical trials and are well funded.
As mitochondria produce the chemical energy store ATP they also generate waste products as a byproduct, in this case highly reactive molecules called free radicals. Free radicals can strike and damage parts of the cell including the mitochondrial DNA (mtDNA), which, due to their close proximity to the source of free radicals, are very vulnerable to these damaging strikes. Damaged mutant mitochondria enter an abnormal metabolic state to remain alive. This leads to cells with damaged mitochondria that dump waste into the circulation causing system wide levels of oxidative stress to rise and driving the aging process.
The solution to this problem is gene therapy to move the mtDNA to the cell nucleus where it will have a far greater level of protection from free radical strikes. The SENS Research Foundation successfully fundraised for the MitoSENS project on Lifespan.io back in 2015. They then followed up with a publication in the prestigious Nucleic Acids Research journal showing their results in September 2016. Thanks to the support of the community the MitoSENS project succeeded in migrating not one but two mitochondrial genes to the cell nucleus, a world first. Since then progress has been rapid and they have now almost migrated 4 of the 13 mitochondrial genes. They are currently refining the process into a standardized therapy.
Our cells have a built-in safety device that causes cells that are dysfunctional and damaged to destroy themselves in a process known as apoptosis. However as we age cells increasingly fail to dispose of themselves in this manner and they enter a state known as senescence. As we age more of these cells build up leading to increasingly poor tissue repair and regeneration. There has been a huge level of interest in senescent cell removal therapies in the last year or two and a number of companies are currently developing senolytics. Unity Biotechnology is taking the first generation of senolytics into human clinical trials this year after being successfully funded by a number of big investors. However the heat is on as other companies are following up close behind with potentially more sophisticated approaches for removing senescent cells such as plasmid based solutions from Oisin Biotechnologies and a synthetic biology approach from CellAge who successfully fundraised on Lifespan.io last year.
Blood sugar and other molecules react with structural proteins in tissues and bond with them creating fused crosslinks. Crosslinks bind neighboring proteins together impairing their movement and function. In the case of the artery wall crosslinked collagen prevents the artery from flexing in time with the pulse leading to hypertension and a rise of blood pressure. The SENS Research Foundation proposes to find ways to break down these crosslinks to restore movement to the structural proteins and thus reversing the consequences of their formation. The problem for many years was obtaining enough glucosepane, the primary constituent of human crosslinks, to be able to test therapies on. Thanks to funding by the SENS Research Foundation progress at Yale University now allows the cheap production of glucosepane on demand, this means that researchers can now test directly on it and find antibodies and enzymes to dissolve the accumulated crosslinks. Yale already has some antibodies against glucosepane, it is anticipated that by the end of the year monoclonal antibodies will be available and there is strong evidence for the existence of bacteria with enzymes that can break down glucosepane.
Misfolded proteins produced in the cell are normally broken down and recycled within the cell, but as we age more and more misfolded proteins accumulate to form sticky aggregates. These misshapen proteins impair cell or tissue function with their presence. This extracellular junk is known as amyloid and comes in a number of types. The work SENS Research Foundation funded at UT Houston in Sudhir Paul’s lab is now in the hands of his company Covalent Biosciences, hopefully we will hear some news from them in the near future. Fortunately a number of alternatives are in development such as the GAIM system that appears capable of clearing multiple types of amyloids included those associated with Alzheimer’s, Parkinson’s and amyloidosis. The AdPROM protein targeting system also holds promise for selectively degrading target amyloids and other undruggable proteins to treat age-related diseases.
Cells have a number of systems for breaking down unwanted materials, the lysosome is one of them. The lysosome can be considered to be a kind of cellular garbage disposal unit which contains powerful enzymes for breaking down unwanted materials. However, sometimes materials are fused together so well that not even the lysosome can break them down. This leaves the unwanted material sitting there and over time more and more of this material accumulates until it starts to interfere with lysosomal function. The solution to this problem proposed by the SENS Research Foundation is to identify new enzymes able to digest these insoluble wastes and supply macrophages and other cells with them so they can break it down. Ichor Therapeutics is taking SENS Research Foundation technology to market for macular degeneration with a therapy that removes a Vitamin A derivative that accumulates in the eye and causes blindness. Ichor has successfully conducted a seed round and is now undertaking a 15 million dollar series A round. The company is less than a year away from human clinical trials.
It is true that the SENS initiative, the Strategies for Engineered Negligible Senescence, has come a long way from its turn of the century origins as a rallying point, a research proposal, and a few like-minded advocates and researchers. After fifteen years of earnest advocacy, fundraising, scientific work, and persuasion, some lines of SENS research are now in clinical trials and commercial development, numerous independent groups are working on SENS or SENS-like research, a great, sweeping, and positive change in the attitudes of the research community towards aging has taken place, and the SENS Research Foundation has a yearly budget of a few million dollars provided by philanthropic donations – a mix of grassroots support by our community, and the greater material support provided a few high net worth individuals. This progress is a big deal, make no mistake: collectively our community has bootstrapped something from nothing, and that something has made and continues to make a great difference to our odds of living to see aging brought under medical control.
Yet this is still the beginning of the story, the opening of the age of rejuvenation, the very first portion of a much bigger picture. A great deal of necessary growth is yet to be achieved. Wherever we stand on the upward curve of bootstrapping and success, there is still a mountain ahead. The yearly funding needs to be hundreds of millions, not a few million. SENS must become the majority concern in the broader research community, not just a handful of labs and a few dozen lines of research. I believe that is is possible for us to create this future, as success in the SENS approach of senescent cell clearance will be proof enough to direct ever more researchers and funding sources towards repair and rejuvenation as a guiding strategy rather than their current approach of tinkering with metabolism to slightly slow down aging.
In any machine, biological or otherwise, repair will almost always have better and more cost-effective outcomes than trying to alter the way in which the machine operates: remove the rust and replace the worn parts rather than merely changing the oil while hoping for the best. This has already been quite adequately demonstrated in the case of aging: repair in the sense of targeted removal of senescent cells has achieved a greater and more reliable impact on aging in a few short years of animal studies, than has been achieved by the far greater, much more expensive, and longer-lasting efforts devoted to calorie restriction mimetic development.
The potential for SENS rejuvenation research is tremendous, and we are just getting started.