The SENS Research Foundation, like the Methuselah Foundation it emerged from, is one of the more important organizations involved in the creation and shaping of the present R&D communities focused on treating aging as a medical condition. In earlier days, advocates and philanthropic programs were attempting to sway the research community (and the world at large) into taking intervention in aging seriously at all. In other words to accept that the evidence was strongly in favor of the plausibility of rejuvenation therapies, that the evidence had been strongly in favor for a long time, and that the long-standing reluctance of researchers and developers to engage in this work was entirely irrational.
That battle was in essence won a decade ago, all over bar the shouting. The research community is now wholeheartedly in favor of the treatment of aging, albeit in a wide variety of ways, not all of which are likely to work. Now advocates and philanthropic programs focus on helping the best and most promising research programs to achieve meaningful progress: provision of funding at early stages, removing roadblocks such as a lack of tooling in the space, giving them the publicity they need, persuading researchers to work on better rather than worse approaches, and so forth.
The best and most promising programs are those that can in principle produce rejuvenation in old people, and the SENS Research Foundation approach to identifying such programs has always been that they must result in periodic repair of the forms of cell and tissue damage that lie at the root of aging. It remains the case that most researchers in the field are not working on potential rejuvenation technologies, but rather on ways to tinker with metabolism in late stage aging that might make it slightly more resilient to damage. Thus there remains a great deal of work to be undertaken by advocates and philanthropists, or indeed anyone who would like to see sizable gains in human longevity sooner rather than later.
At our 2013 conference at Queens College, Cambridge, I closed my talk by saying, "We should not rest until we make aging an absurdity." We are now in a very different place. After a lot of patient explanation, publication of scientific results, conferences, and time, our community persuaded enough scientists of the feasibility of the damage repair approach to move SENS and SENS Research Foundation from the fringes of scientific respectability to the vanguard of a mainstream community of scientists developing medical therapies to tackle human aging.
Then we made the same case to investors and entrepreneurs; now, rejuvenation companies built on or inspired by our research are part of a robust ecosystem of basic science and biotech venture capitalists advancing the mission. After serving on the board for ten years, it was great to join the team full time last fall. While resources affect the pace of our progress, so do regulations and other government policies. So we began a lively dialogue with policymakers by inviting discussions of regulatory reform at our conferences and by hosting the Deputy Secretary of Health and Human Services, Eric Hargan, at our January health care event in San Francisco. More and more influential people consider aging an absurdity. Now we need to make it one.
Stepwise Visualization of Autophagy for Screening Remediation of Intraneuronal Aggregates
People often assume that an increase in autophagy automatically results in an increase in the ultimate degradation of unwanted molecular waste, but in fact the word only refers to the delivery process: it's possible to have an increase in autophagy (or in markers of autophagy) that is ultimately futile. Typical methods of testing autophagy activity can fool investigators into thinking that the affected cells are engaged in robust and successful autophagy, when instead they are signs of futile autophagy and associated with cellular dysfunction. To sort out this confusion, determine what's really being delivered to the lysosome, and pinpoint disruptions in the autophagy process, Dr. Andersen's team team has been developing a system to visualize each of the key steps along the way.
Retrolytic Therapy to Destroy Cells with Reactivated "Jumping Genes"
With SRF sponsorship, Dr. Gudkov's lab is developing a proof of concept for future rejuvenation biotechnologies that will ablate cells with active retrotransposon activity. For this initial demonstration, Gudkov will use a transgenic "suicide gene" system similar to the INK-ATTAC system that first demonstrated the rejuvenating effects of destroying senescent cells in aging mammals. In this case, the suicide gene system will be triggered by the activation of the interferon response to retroviral reactivation instead of a senescence-associated gene. Just as INK-ATTAC paved the way to the development of today's senolytic therapies (drugs and other approaches that destroy senescent cells), this suicide gene system for the elimination of cells harboring reactivated retrotransposons holds the promise of paving the way for similarly-powerful future "retrolytic" therapies.
Functional Neuron Replacement to Rejuvenate the Neocortex
The maintenance of the brain against degenerative aging processes poses extreme challenges. Only recently have researchers succeeded in integrating new neurons into areas of the brain involved in cognitive functions. Surgically transplanting a small number of neuronal progenitors into a local brain structure has been done to date but cannot realistically scale to the sheer size of the brain, or keep up with the rate of age-related neuronal loss. Therefore, maintenance of the aging brain requires a system for ongoing dispersal of neuronal precursor cells across the brain. To accomplish this goal, SENS Research Foundation is supporting Dr. Jean Hébert's innovative strategies to overcome these critical challenges. To enable the dispersal of replacement neurons noninvasively and throughout the brain, Dr. Hébert's team will next take advantage of the unique properties of microglia, the specialized macrophage immune cells of the brain. Unlike neurons and their precursors, microglia are highly motile cells, able to disperse widely throughout the brain. Hébert's strategy is to transplant microglia into the brains of mice and then reprogram the new microglia into cortical projection neurons after they disperse throughout the brain.
Engineering cyclodextrins for the Removal of Toxic Oxysterols as a Treatment For Atherosclerosis and other diseases of aging
Dr. O'Connor's team has created a family of novel cyclodextrins that are able to selectively remove toxic forms of cholesterol from early foam cells and other cells in the blood, thus forming a potential treatment for atherosclerosis. In 2019, SENS Research Foundation announced the launch of Underdog Pharmaceuticals, Inc. (Underdog), a pharmaceutical company focused on the development of this program for disease-modifying treatments for atherosclerosis and other age-related diseases. Its co-founders are Matthew O'Connor, Ph.D., and Michael Kope, formerly the Vice President of Research and the founding Chief Executive Officer, respectively, of SRF. Mike and Oki have worked incredibly hard to transition a piece of SRF's basic research to the next level, stepping into the private sector and creating a treatment for age-related disease based on one of SRF's successful proof-of-concept programs. Ten or twenty years ago, cardiovascular disease research meant developing better stents or bypass techniques; Underdog aims to ensure that atherosclerosis won't even exist in the future. All of us at SRF wish Mike and Oki success in this endeavor.
Targeting Secondary Senescence
Scientists have relatively recently discovered the phenomenon of secondary senescence. For reasons which we are only beginning to understand, existing senescent cells can cause other cells in the body to become senescent. Although this research is still in an early stage, it is beginning to appear that secondary senescent cells behave differently from primary senescent cells: they produce less SASP, but more fibrillar collagens - something that is normally suppressed in primary senescent cells. Granted their differences in origin and function, might secondary senescent cells also be differentially susceptible to senolytic therapies? For instance, might they be resistant to senolytic drugs that are effective against primary senescent cells, requiring a new generation of targeted "secondary senolytics" to eliminate - or might they be exceptionally susceptible to particular such treatments? SENS Research Foundation Forever Healthy Postdoctoral Fellow Tesfahun Admasu's work seeks to find answers to these questions.
Target Prioritization of Tissue Crosslinking
One cause of stiffening in long-lived tissues is crosslinking, where one strand of structural protein becomes chemically bound to an adjacent strand, limiting the range of motion of both strands. Prior SRF-funded work in Dr. David Spiegel's lab at Yale paved the way to the discovery of the therapeutic glucosepane-cleaving enzyme candidates that our startup company Revel Pharmaceuticals is now working to advance into functional rejuvenation biotechnologies. However, AGEs are not the only cause of crosslinking in aging tissues. The sheer number of a given type of crosslink is moreover not necessarily a good parameter for determining how we should prioritize that crosslink type as a rejuvenation target. Recognizing the importance of prioritizing our targets, SRF is funding a systematic study in "normally"-aging, nondiabetic mice by Dr. Jonathan Clark at the Babraham Institute in Cambridge. These mice are fed diets containing labeled amino acids, which are then incorporated into extracellular matrix proteins during synthesis. This allows Dr. Clark's group to track the rate at which proteins are synthesized, crosslinked, and replaced over time.