Fight Aging!

I recently attended the 2020 Longevity Therapeutics conference in San Francisco. I presented on the work ongoing at Repair Biotechnologies, but as is usually the case the more important parts of the visit took place outside the bounds of the conference proper. Longevity Therapeutics is one of the four or five core conferences for the longevity industry, at which you'll meet many of the early participants - a mix of scientists, entrepreneurs, and investors, and patient advocates. As such, most of the conference goers have already seen my updates, or are otherwise aware of the Repair Biotechnologies programs aimed at thymic regeneration and reversal of atherosclerosis. This year was heavily biased towards the entrepreneurial component of the community. It was even the case that most of the scientists attending were presenting in the context of a company that is advancing their work towards the clinic. As the longevity industry expands, ever more researchers in the aging field are finding the opportunity to start a company, or otherwise hand off their work for clinical development.

The first day was a lightly populated set of workshops prior to the conference proper. In the morning, Aubrey de Grey of the SENS Research Foundation and AgeX Therapeutics gave his usual overview of the state of rejuvenation research and development, with a little more emphasis than usual on clinical development and investment in the field. Irina Conboy discussed the plasticity of aging; she is one of the more noted researchers involved in the modern investigations of parabiosis, in which old and young mice have their circulatory systems linked. She gave a tour of differences observed in old mice during parabiosis, such as improved liver regeneration. The argument of beneficial factors in young blood versus detrimental factors in old blood has resolved, by the sound of it, to the conclusion that both mechanisms are relevant - there are a lot of different factors, of different importance. She noted that she is starting a company to push forward some of her work on upregulation or downregulation of factors identified in parabiosis, particularly the combination of oxytocin and TGF-β. Michael Fossel talked about the hallmarks of aging and what to do with them. His point was that metabolism and aging are enormously complicated, forming a system that exhibits risk factors rather than deterministic behaviors. The focus should be on finding the best point of intervention, which is not the same thing as understanding the system. Greater understanding only makes finding the best point of intervention easier, it isn't absolutely required.

The afternoon was more focused on clinical translation, with presentations from companies further along in the process of conducting trials with the FDA. Mark Allen of Elevian talked about indication choice as a challenging process for companies targeting aging. Elevian is a GDF11 company, and they presently think that prior issues with contradictory results for GDF11 delivery in animal models were due to poor manufacture of the protein. Indication choice is challenging for therapies intervening in aging because so many different indications can be considered, but most are dead ends. It is very important to consider how the choice of indication affects time to market: one is looking for short treatments that can produce large effects. Further, if you want the FDA on your side, you really have to go after large unmet needs for serious diseases. The Elevian team used a matrix/scoring approach to assess different indications. Outside expertise is vital; you can't do this yourself.

Elizabeth Jeffards and Erin Newman from Alkahest further elaborated on this process of indication selection, and then moved on to talk about how to run trials. Their high level point was that the operation of trials becomes your whole company, determining everything about how you are seen and how you proceed. The two talked about the central matter of payer willingness to pay for your therapies - whether insurance giants, Medicare, and other entities will toe the line. This is a very important matter, at all stages of the process of figuring out which indication to pursue. They also emphasized the need to build a very specific target product profile, the exact cost and performance of your therapy, well in advance of any sort of data. Another vital issue is manufacturing: getting the timing right, given the lengthy duration of GMP manufacture, and the huge cost of that process. This is challenging and needs very careful management. Peter Milner of Retrotope talked about their orphan disease trials, and reinforced the points already made. Retrope uses deteurium stabilized lipids to treat neurodegenerative conditions in which lipid peroxidation is a serious concern. In talking about about the Retrotope clinical trials, he again pointed out that cost and time are very important in their choices of indications - one has to to look for large effects achieved in quick trials.

The first day of the conference opened with a keynote by Nathaniel David of UNITY Biotechnologies. He surveyed the common approaches to research aimed at intervention in aging, that small changes between species biochemistry leads to large changes in species life span, and so forth. Regarding UNITY, he discussed their human data on the performance of senolytics for osteoarthritis and for degeneration of the retina, such as dry macular degeneration. They are in phase II for osteoarthritis, with data coming out late in 2020. For the eye, they are still working on phase 1 safety data, also coming out late 2020. They are also in the earlier stages of developing senolytic treatments for lung and kidney diseases.

Following that, Joan Mannick of ResTORbio opened her presentation by lauding mTORC1 as a target, pointing to the large body of research in short-lived species. Following failure on their phase III trial for reducing influenza incidence, they are now focusing on neurodegenerative disease, particularly Parkinson's disease. They believe that raised autophagy via mTORC1 inhibition may help with aggregates in these conditions, and discussed some of the supporting evidence in animal models. Peter Fedichev of Gero presented on their AI program for small molecule drug repurposing and discovery. Based on their models of biochemical data from mice and humans, they divide aging into two overlapping processes that they call "aging" and "frailty" - these are names for portions of a data model, and don't necessarily map well to the common meanings of the words. Mice and humans have quite different proportions of "aging" versus "frailty". Gero has new data from lifespan and rejuvenation studies using compounds that they intend to repurpose: they have achieved some degree of slowing or reversal of aspects of aging via their drugs in mice. This essentially shows they can pick drugs that perform comparably to some of the historical efforts to achieve this sort of outcome, and can do so faster than was possible in the past.

Gino Cortopossi of UC Davis is working on new approaches to upregulate mitochondrial function. He discussed how his group carried out the discovery of drug candidates to try to target mitochondrial function, SHC, and MTORC1. This presentation was an exercise in thinking about how to test interventions of this nature, what sort of a path leads forward from there to the clinic, and how to organize a handoff from academia to Big Pharma. Hanadie Yousef of Juvena Therapeutics talked about their AI-driven program of mining the secretome of pluripotent cells. The Juvena staff are searching for secreted molecules that can delivered as therapies to upregulate regenerative and stem cell capacity in old people. Their initial focus is on muscle regeneration in the context of age-related sarcopenia. In one of the more interesting presentations of the day, Matthias Hackl of TAmiRNA talked about biomarker development in the microRNA space. The TAmiRNA folk think that they should be able to use a blood sample to produce simultaneous measures of senescent cell burden in many different tissues via assessment of circulating miRNAs from the senescence-associated secretory phenotype (SASP): each tissue has a signature. They are not quite there yet, but this will be very useful if it works out. Dana Larocca of AgeX Therapeutics talked on the topic of exosomes. That AgeX is focused on production of useful cell lines via induced pluripotency gives them a good head start on the production of useful exosomes via harvesting cell cultures of those cell lines. They are presently engaged in the search for interesting exosomes that might form the basis for therapies that make adult stem cells more active.

Jay Sarkar of Turn.bio discussed their approach to transient epigenetic reprogramming in order to force cell function to become more youthful. They use mRNA for reprogramming, as they feel it gives them greater control, and precise control is very important in their work - they must not push cells all the way into pluripotency, just shock them into better operations, and there is a fine line between those two outcomes. The Turn.bio staff are using in vitro cell data to suggest that they can affect various hallmarks of aging: changing certain cell properties and the overall transcription landscape. The approach doesn't lengthen telomeres, which is interesting; the most important thing it does, I would say, is to restore mitochondrial function. He showed data for chondrocytes, relevant to osteoarthritis, and the Turn.bio team are also trying a cell therapy approach on this front, to reprogram cells and then transplant them to see if they help. Additionally, they have worked in skin models to show reversal of aspects of aging there. Turn.bio is one of a growing number of companies working with Entos Pharmaceuticals to produce a non-toxic lipid nanoparticle vector to deliver their therapy in vivo. Given that, it isn't surprising that that they are also working with Oisin Biotechnologies, who also use the Entos Pharmaceuticals platform, to see how senolytics plus reprogramming work in synergy.

Rich Allsop of University of Hawaii talked on the role of FOXO3, one of the few robustly longevity associated genes in humans, in influencing telomere shortening and inflammaging. It touches on the IGF-1 pathway, and a variant is associated with greater longevity in humans. These researchers think that the behavior of the variant is more to do with enhancer or promoter effects on gene expression, not functional differences in the protein, as the difference is in a non-coding region of the gene. There is some question as whether inflammation causes a difference in the pace of telomere shortening, such as via faster replication of immune cells in response to inflammatory signaling, or whether the relationship functions in a different way. Michael Fossel of Telocyte discussed his view on telomeres, cellular senescence, and telomerase gene therapy. He argues that the data shows that you need to increase telomere length to a large degree in order to see reductions in cancer risk, meaning lots of telomerase, not just a little - too little and there will be more cancer. His company is presently looking for funding to run an Alzheimer's disease trial of telomerase gene therapy; they have everything planned, and just need the backing.

Steve Turner of InVivo Biosystems presented on a system that can be used to determine quickly, say in 3 months, whether or not a therapy will extend lifespan and healthspan. To achieve this result they use C. elegans and zebrafish, and assess omics results, with some degree of automation in their platform. In a related presentation, Gordon Lithgow of the Buck Institute outlined their work on small molecule discovery with a C. elegans platform. A fair number of varied approaches to cost-effectively use these short-lived species in conjunction with automation, omics, and AI are out there under development these days. Kristen Fortney of Bioage Labs talked on their AI-driven discovery in human aging omics data, in search of pathways that can be drugged. They take a holistic view of aging: don't study age-related diseases, study aging as a whole, look for important processes. Given pathways, they perform screening in vitro, then take drug candidates to a sizeable vivarium of 3,000 mice (expanding to 12,000 all too soon), and test the outcome there. They outlined a few example targets and the data supporting their ongoing work, including approaches to reduce neuroinflammation. Andrea Maier of the University of Melbourne talked at a high level on the development of potential aging-targeting repurposed drugs in Australia. This was a very nuts and bolts outline regarding how one plans and conducts human trials for specific age-related diseases. They were largely focused on lifestyle intervention, and are only now starting to think about drugs. Rounding out the first day, Wim von Schooten of Teneobio presented on the use of a CD38 inhibitor as a way to upregulate NAD+ levels and mitochondrial function. CD38 is somewhat connected to the proximate causes of NAD+ reduction in aging mitochondria, but it has other roles as well. It is also anti-inflammatory. CD38 is upregulated with age, in concert with NAD+ drop and inflammation rise, and the position in this presentation is that CD38 is causal of NAD+ decline.

The second day of the conference kicked off with a presentation by Sergio Ruiz on the topic of the Methuselah Fund and their progress to date in supporting new and important companies in the longevity industry. He gave a general overview on the state of investment in early stage companies in the field: what investors are looking for; how to transition from lab to clinic; the recent evolution of the longevity industry and the field of aging research. He noted that this is a huge opportunity for changing the human condition, not just a chance for a sizable return on investment. The team is presently working on raising their second fund. The first fund writes $50k-$500k checks, second fund will be much larger and write $1m-$5m checks.

Ronald Kohanski of the National Institute on Aging gave the NIA/NIH perspective on rejuvenation and accelerated aging as therapeutic targets. They see the Interventions Testing Program and other programs as ways in which the NIA supports industry. He noted a range of ongoing work at the NIA that connects to the hallmarks of aging. They are starting to think about using omics data from the Interventions Testing Program and other studies to better understand what is taking place in aging-related pathways, as well as to develop ways to measure rejuvenation and aging. The presentation mostly dwelled on parabiosis and small molecules that slow aging as interventions to consider in this context. Nir Barzilai of the Albert Einstein College of Medicine followed to talk about the challenges inherent in making therapies to target aging or age-related diseases. The first problem is that animal models are not great, there is too much failure in translation to human medicine. Then there is the issue of payers (insurance companies, medicare, and so on) that don't want to pay for interventions that slow aging, which is related to the challenge of there being no FDA-approved indication for aging. The lack of an indication is largely why payers will not pay, even if therapies could be approved in some useful way. He mixed this in with his usual talk about centenarians and data on their health habits, genetics, and so forth.

Kevin Perrott of OpenCures presented on collecting data from people who are trying interventions themselves, self-experimenters, to try to reduce the time taken to develop new therapies. He is conducting proteomic analysis of blood samples from people in the self-experimentation community to measure outcomes, and the OpenCures team are also carrying out volunteers studies of supplement-regulated compounds, somewhat similar to phase 1 trials in organization, with proteomic measurements to assess effects. Julie Andersen of the Buck Institute talked about cellular senescence as a driver of Alzheimer's disease - something I would like to see a lot more work on, given the potential for meaningful benefits to patients. She noted the evidence for senescent glial cells, such as astrocytes, to contribute to neurodegenerative pathology. It is now thought possible for post-mitotic neurons to undergo senescence as well, contrary to earlier dogma. That might present a challenge, but equally obvious issues with cognitive function haven't manifested yet in animal studies of senolytics. She presented in vitro evidence for amyloid-β to cause senescence in brain cells, and suggested that the spread of senescence via the SASP occurs without amyloid-β in the later stages of the condition. The initial presence of amyloid-β is required, but not thereafter, and might be why removing amyloid-β doesn't help once this process is underway.

Richard Marshak of Torcept Therapeutics undertook a discussion on how to go about rational drug development with aging as the target. The company conducts drug discovery of mTORC1 inhibitors, and he talked about their pipeline and evidence. There is still skepticism from Big Pharma regarding the whole of the longevity industry: there are no clear endpoints; the technical and regulatory risk is far greater than Big Pharma entities are usually prepared to engage with; and the expense of testing against aging as a target is believed to be high. Once again this included a discussion of payers versus regulators, and what these two groups are looking for. Payers are interested in extending healthy longevity, it is worth bearing this in mind - there are strong economic incentives here that may help to overcome other issues. The development of endpoints for interventions in aging is important, since we can't use aging itself right now. Yet surrogate outcomes (measurements of biomarkers rather than patient outcomes) are not popular with anybody in the regulatory system at this time.

Marco Quarta at Rubedo Life Sciences presented on their small molecule discovery of senolytic and anticancer compounds. They are at the preclinical stage and would like to start looking at other cell changes that occur with age as well, such as loss of stem cell function. They are claiming a 60-70% clearance of senescent cells in multiple tissues via their lead senolytic, which is larger than most of the published literature to date - but it is hard to say how this compares with the state of the art in the various companies working on new senolytics. A range of other mouse model data on toxicity, safety, and effectiveness was presented. Andy Schile of Jackson Laboratory gave a plug for their aged mice, a source for studies. He surrounded that with examples of some of their studies of mice at different ages, presenting data on their usefulness in various models of age-related disease and dysfunction. Pan Zheng from the University of Maryland Baltimore talked about the role of CD24 in the inflammatory response to tissue damage, such as in the context of graft versus host disease, for example. This research group is attempting to influence the CD24 pathway to reduce inflammation in bone marrow grafts, HIV patients, and during immunotherapy. They have a CD24 fusion protein that works via affecting immune checkpoints to dampen the response.

Jean-Marc Brondello of ISERM discussed cellular senescence as a cause of osteoarthritis, with a focus on the details of the manifestations of the condition and how senescence contributes to these issues. This team is processing omics data to identify possible new senotherapeutics that might address the issue. John Lewis of Oisin Biotechnologies gave the usual presentation on the Entos Pharmaceuticals lipid nanoparticle platform and its application as a senolytic therapy when delivering a suicide gene therapy triggered by expression of p16 or p53. An important point emphasized here is the exceptional safety profile of these nanoparticles - massive doses can be supplied to mice and other mammals with no signs of toxicity. Andrei Gudkov at Genome Protection discussed retrotransposons and their role in aging. Of particular interest is that retrotransposon activity drives chronic inflammation via cellular senescence. This team is developing therapies to try to ameliorate these issues. He presented an interesting view of aging as a species-specific cliff of mortality, and argues that DNA damage (i.e. retrotransposon activity) is the cause of the cliff, via production of chronic inflammation at a time dictated by loss of suppression of retrotransposon activity. Genome Protection studies retrotransposons in dogs, as breed variations in lifespan may be largely caused by retrotransposon based changes - the differences in genetics between dog breeds tend to cluster appear in locations connected to retrotranspon activity. Lastly, Lewis Gruber from SIWA Therapeutics presented on their program focused on a senolytic monoclonal antibody. They originally started out by targeting oxidative stress and glycolysis: these aspects of cell dysfunction have a common advanced glycation endproduct surface marker for a monoclonal antibody to bind to. Given that binding, immune cells then destroy the errant cell. He pointed out that these marked cells are largely senescent, but others might only be dysfunctional. That can include cancerous cells.

All in all it was a interesting event, a good chance to catch up with existing members of the community and meet some new faces. If one has an interest in joining the longevity industry in some way, Longevity Therapeutics should be on the list of conferences to attend, along with Undoing Aging in Berlin, Ending Age-Related Diseases in New York, and Longevity Leaders and the Longevity Week events in London.