The latest annual report from the SENS Research Foundation is out, covering progress in 2017 and early 2018. The SENS Research Foundation remains one of the very few philanthropic organizations focused on speeding the development of rejuvenation therapies - something we hope to see change in the years to come, as more support arrives for this field. The foundation staff use the charitable donations provided by our community to fund research programs specifically focused on areas of biotechnology that are presently blocked or neglected, but that can potentially give rise to ways to repair, remove, or work around the cell and tissue damage that causes aging. They also support networking, advocacy, and conference series designed to build bridges between academia and industry in order to smooth the road towards commercial development of advances developed in the laboratory.
Along with the Methuselah Foundation, where the SENS rejuvenation research programs started, the SENS Research Foundation has done a great deal to change the way in which the scientific community and broader public view aging. Back at the turn of the century, when the SENS program was proposed, and Aubrey de Grey presented his synthesis of existing evidence for seven broad categories of molecular damage that caused aging, the leaders in the research and funding communities actively suppressed any effort to work on or discuss the treatment of aging as a medical condition. It was career suicide to openly work towards that goal. The change achieved since then has been profound, and now researchers openly debate how best to go about treating aging to extend healthy life spans. This required a great deal of hard work.
A few strands of rejuvenation research have moved into clinical development in recent years: the removal of senescent cells, and clearance of a few kinds of harmful metabolic waste. As a part of its efforts, the SENS Research Foundation can now point to the ongoing development of startup biotechnology companies that it helped to seed fund, in some cases in partnership with the Methuselah Foundation. We will be seeing more of this in the years ahead: successful young companies can typically raise a great deal more funding than is available via philanthropy, and their efforts also go a long way towards attracting more validation and attention to the field.
The valley of death - the chasm between innovation and availability that has become such a common theme in drug development - is especially wide for the field of rejuvenation biotechnology. Besides the time and resources required to develop any medicine, the few who initially strove to develop this field faced the added challenge of demonstrating that we could feasibly intervene to prevent age- related disease by redressing the underlying damage that causes such disease. There is scarcely a biotech organization that hasn't used, at some point, a 'bridging the gulf' metaphor to address the valley of death. But it has been such an integral part of our identity that we built it into our brand; the multi-colored ribbon of our logo having been designed to evoke both double-helix and suspension bridge imagery (and yes, it's always had seven twists).
Upon the launch of his project to build the Golden Gate Bridge, Chief Engineer Joseph Strauss had this to say: "It took two decades and two hundred million words to convince people the bridge was feasible." We have at times wondered whether even that would be sufficient. But with the diligent efforts of our own research teams and those of a growing number of institutions, the question of feasibility has increasingly fallen away. Today we see our research programs successfully translating into development, our former students becoming rejuvenation biotechnologists and developers, new collaborative energy from the investment arena, and the groundwork being laid for regulatory models for rejuvenation interventions.
Antoxerene, a portfolio company of Ichor Therapeutics, is a small molecule drug discovery company that focuses on molecular pathways of aging. To our knowledge, Antoxerene is the first and only company with small molecule hits on the p53/FOXO4 pathway, which has been implicated in cellular senescence. Antoxerene is developing these hits for eventual clinical use.
Lysoclear, a portfolio company of Ichor Therapeutics, is an ophthalmology company developing an enzyme therapy for age-related macular degeneration and Stargardt's disease. In 2017, the company completed pivotal proof-of-concept studies with its first generation enzyme lead and conducted extensive mechanistic work to clarify the role of retinal lipofuscin in the onset and progression of macular degeneration. These results have been submitted for peer-reviewed publication. Lysoclear is now optimizing its enzyme into a drug candidate in preparation for IND enabling studies.
Oisín is developing a DNA construct that recognizes that a cell has become senescent and then destroys it, and safely and efficiently delivering this construct into cells throughout the body. Both goals have been achieved in pioneering proof of concept experiments in 2016. Now they are embarked on experiments that will show improvements in both healthspan and lifespan in model organisms from mice to primates.
Arigos has made great strides towards the banking of human organs, demonstrating functional and structural recovery of similarly-sized tissues from below -120°C. Their ability to cryopreserve large, complex tissue structures is a breakthrough in medical research. Stable banking for larger tissue structures and organs could more than double the number of transplants performed each year and would eliminate five of the current organ waiting lists within a few years.
The MitoSENS team is working on a potential rejuvenation biotechnology to sustain and recover electron transport chain (ETC) function: allotopic expression of functional mitochondrial genes. Allotopic expression involves placing "backup copies" of all of the protein-coding genes of the mitochondria in the "safe harbor" of the nucleus, which can then deliver the proteins mitochondria need to build their ETC and continue producing energy normally, even when the original mitochondrial copies have been mutated. The team is working to establish a "landing pad" in mouse cells to enable reliable and safe gene therapy for animal studies, via the Maximally-Modifiable Mouse Project. They expect to soon begin preliminary in vivo testing of allotopic ATP8 in transgenic mice. Meanwhile, they are also looking to expand the strategy to other mitochondrial genes and further improve allotopic expression of the ATP6 gene.
A major cause of crosslink accumulation in aging is Advanced Glycation Endproducts (AGE), and one AGE in particular - called glucosepane - is currently thought to be the single largest contributor to tissue AGE crosslinking, with consequences such as arterial stiffening. The Yale team is developing new reagents and approaches to accelerate glucosepane research. They now are able to synthesize all three conformational variants (diastereomers) of glucosepane that may occur in vivo. They are also working to generate antibodies that can then be used to label glucosepane crosslinks in tissue samples and in vivo. Further, the Yale team has identified some potential glucosepane-breakers, about which we hope to be able to make further announcements this year pending publication in a peer-reviewed journal.
One of the reasons why senescent cells secrete inflammatory signals is to attract Natural Killer (NK) immune cells, which then clear senescent cells from the tissue. Despite this, senescent cells accumulate over the course of the lifespan. A critical question is therefore that of how some senescent cells are able to escape immune surveillance and what might be done to overcome their defenses. Dr. Judith Campisi, a renowned pioneer in senescence research, is answering this question and developing strategies to enhance immune clearance of senescent cells. Campisi's group has already discovered that one of the key NK cell binding markers on the surface of senescent cells begins to disappear within weeks of the cell becoming senescent. Without this marker ligand, NK cell binding cannot occur, and the NK cells' killing ability cannot be unleashed. Early results suggest some potential strategies for restoring NK cell immunosurveillance of senescent cells.
Aggregates composed of aberrant tau protein accumulate with age, both inside and outside of neurons. These aggregates are an important driver of neurodegenerative diseases of aging. One possible basis for this intracellular accumulation may be as a consequence of age-related lysosomal dysfunction that is driven by the accumulation of other kinds of intracellular aggregates. As such, this deleterious accumulation might be reversed if lysosomal function could be restored. This line of investigation will inform strategy: do we need a custom solution just for intracellular tau aggregates, or will clearing other age-related lysosomal junk be sufficient to restore an existing capacity to eliminate these aggregates? The Andersen lab is testing this possibility using neurons that express mutant versus wild-type human tau.
Atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity but ultimately fall prey to that same toxicity themselves. Dr. O'Connor's team has identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from human blood, which would help combat the development of atherosclerosis. They have been testing its effects and those of closely-related compounds in human blood samples, seeking potential modifications and combinations that would maximize selectivity for toxic cholesterol byproducts while leaving native cholesterol alone.