Fight Aging!

Repair Biotechnologies was invited to present at this year's Rejuvenation Startup Summit in Berlin, and so my CSO Mourad Topors and I attended. There were more people present this year than were at the already busy 2022 event. This is perhaps an indication of a still growing interest in the longevity industry as it expands, particularly given the present poor market for investment in biotechnology companies. Investors are tending to stay home this year, but nonetheless there was a fair sized crowd in attendance.

Michael Greve's Forever Healthy Foundation hosts the Rejuvenation Startup Summit, and he gave the opening talk, framing the point of the exercise. The longevity industry will clearly become one of the world's largest industries, growing to become the majority of all medicine, given that every older individual is a potential customer. The hundred or more biotech startups that presently make up the longevity industry will collectively demonstrate that this field works, that it is viable, that we can slow and reverse aging. The first proven therapies will usher in a great increase in interest, investment, and participation in the longevity industry. The purpose of this conference series is to help to make that future happen: networking makes the world turn, particularly in the world of biotech investment.

The keynote was provided by Mehmood Khan of the Hevolution Foundation, slowly but steadily deploying Saudi Arabian sovereign wealth into aging research and the longevity industry. Hevolution is a non-profit organization, and plans to put the returns from its investments into further research and development to advance the field. The organization has a fairly conservative viewpoint that is focused on addressing the failure of increases in healthy life span to keep up with overall life span - a focus on compression of morbidity. The financial burden of a growing older population is unsustainable, the existence of the present demographic transition to a larger older population is a driving concern. The current approach to age-related disease isn't working and must change. This conservative viewpoint is one that sees it as very hard to make a gain of few years of healthy life when that gain must be made across the population as a while. Making the technology is perhaps the easier part when compared against the social, realpolitik considerations of how to scale the technology and provide access to it as a public health measure, a low cost therapy. This philosophy explains much of why they focus on the technologies and approaches that they do: mTOR inhibitors that might add a year of life at low cost can better meet their goals than the development of much more advanced therapies that could achieve greater extension of life, but would require decades of work to bring down in cost and scale out to mass availability. Khan made the point that scaling requires the participation of Big Pharma, but Big Pharma is not yet a part of the longevity industry; bringing them into the fold is a task yet to be accomplished. He closed by noting the scale of the disconnect between the cost of aging and the funds available for research. Hevolution has provided $250m in the past 18 months to research institutions that include the Buck Institute, making them the second largest source of funds after the US government - and this is woefully little for the task at hand.

Otto Kanzler of Rockfish Bio opened with an outline of just how bad degenerative aging is: the cost of coping, the disability, the mortality, the lost productivity. The company works on clearance of senescent cells, but while noting that senolytic therapy development is overall very promising, there are barriers to clinical translation. Senescent cells differ considerably by origin, tissue, and stage of senescence. Thus first generation therapies are not effective in clearing all senescent cell types, not selective enough. Further, indication choice is a challenge for any senolytics company, as it might initially seem that there are many options, few are in fact good options from the point of view of cost, difficulty of the discussion with regulators, ability to directly connect senescence to disease mechanisms, and so forth. A big problem is that there are no good non-invasive biomarkers for the burden of senescent cells, either globally or in specific tissues. The company's development program is derived from the realization that senescent cells have increased phospholipase A2 (PLA2) activity. PLA2 is an inducer of apoptosis, but senescent cells convert PLA2 to evade that fate. This is similar to a number of other mechanisms in senescent cells: the cells appear primed for apoptosis, but actively resist it. Rockfish Bio targets this PLA2 conversion with a small molecule, selectively inducing apoptosis in senescent cells as a result. Treatment of mice has produced an extension of life. Rockfish Bio is also collaborating with another industry company to produce a biomarker based on circulating miRNA levels that can measure burden of senescent cells.

Marco Quarta of Rubedo Life Sciences, another senolytics company, also noted the heterogenity of the senescence state, and the problems that this causes in the search for effective therapies. Rubedo has create a drug discovery platform to identify targets for different senescent cell types, and have built up a portfolio of targets and drug candidates. They recently raised significant funding for their first clinical program, focused on skin condition such as atopic dermatitis and psoriasis in which senescent cells are likely important, and where topical therapies can be applied. Like other senolytics companies Rubedo is motivated by the poor selectivity of existing therapies like the dasatinib and quercetin combination, and the off-target effects on non-senescent cells. The goal for Rubedo is to produce drug candidates that are far more selective for specific subsets of senescent cells. At this point, the company expects to start clinical trials in 2025.

Alexander Schueller of cellvie discussed the origins of the company's work on mitochondrial transplantation. Mitochondrial transplantation was used in a clinical trial for children with ischemic heart injury that put them on life support, and the results demonstrated that this approach can work to prevent death and permanent injury. The company was formed to broaden the use of mitochondrial transplantation for all forms of ischemia-reperfusion (IR) injury. A key part of IR injury is dysfunction and damage to mitochondria, but timely delivery of replacement mitochondria prevents much of the cascade of damage resulting from IR injury. The company aims at kidney transplantation as first IR injury situation, as preserving the function of donor kidneys provides the fastest path to a clinical proof of concept that will encourage others to expand this field. The company is presently working towards the development of good manufacturing practice (GMP) protocols for manufacture of harvested mitochondria, with the aim of moving from the use of autologous mitochondria to off the shelf mitochondria that are frozen for storage. Tests have been conducted in pig models that undergo 90 minutes of ischemia to the kidneys followed by treatment with human mitochondria. Biomarkers of kidney function have shown considerable improvement in the treated pigs. Schueller commented on some of the challenges inherent in obtaining funding, in part because the mechanisms underlying the benefits of mitochondrial transplantation are not fully understood. The company has thus been working on obtaining a better understanding, and has shown that uptake of new mitochondria via endocytosis triggers both mitophagy and mitogenesis, improving the situation for native mitochondria. This may not be the only mechanism. The company has also conducted proof of concept research into using mitochondria as a vector for gene therapy, as mitochondria tend to accumulate in the first downstream major organ after intravenous delivery.

Greg Fahy of Intervene Immune gave an update on their work on the reversal of thymic involution. The thymus atrophies, first after puberty, and then more slowly throughout the rest of life, leading to a near complete lack of active tissue as early as age 50 in many cases. The capabilities of the adaptive immune system slowly collapse, lacking the supply of new T cells generated in the thymus - and so the risk of death from immune-related causes rises precipitously after age 50. Thymus transplant from young donors to aged animals has been shown to extend life and restore immune function. Intervene Immune used a growth hormone / DHEA / metformin combination in small human trials, the choice of approach chosen in part to try to gain a rapid approval from regulators. The results from the first TRIIM trial were published in 2019, and included modest reductions in extrinsic and intrinsic epigenetic age. TRIIM-XA was an extension and expansion of that trial, including 26 participants. It is now complete and results are being analyzed. The COVID-19 pandemic occurred during TRIIM-XA, and Fahy speculated on whether this would have had any impact on the results via consequences of vaccination. In preliminary data, TRIIM-XA showed epigenetic age and phenotypic age reversal in a number of different clocks, as well as lower inflammatory markers, increased recent thymic emigrant naive T cells, improved strength and fitness as measured via exercise tolerance, standing test, and VO2max, and lowered body fat percentage and blood pressure. The company is starting to consider adding more agents to the protocol; Fahy tested the addition of a new option on himself recently with positive results.

Eric Verdin of the Buck Institute for Research on Aging gave the second keynote, a selection of ongoing work at the Buck Institute and its relevance to geroscience. He started with the role of senescent cells in aging via their contribution to chronic inflammation and the generation of secondary senescent cells via paracrine signaling. An important implication is that senescent immune cells generate secondary senescence in tissues throughout the body, linking immune aging to near all other aspects of aging. One of the Buck Institute projects focuses on characterizing and measuring senescent cells in the immune system, and finding ways to address it. The researchers have discovered considerable complexity over the course of aging in the changing populations of immune cells of various types and behaviors. Generic markers of cellular senescence show that large proportions of some subpopulations of immune cells have become senescent, for example up to 40% of some memory T cells. These markers of senescence need to be improved upon, however, given the diversity of senescent states. Verdin then moved on to discuss the buildup of lipofuscin with age. The researchers see it as a marker of senescence, at least in the immune system - it is actually a marker of lysosomal stress, characteristic of senescent cells. Their data demonstrates a correlation between lipofuscin burden, age, and other markers of senescence status in T cells. This detailed assessment of immune cell populations has also shown that epigenetic clocks produce different results in different subpopulations of immune cell. As a result, the clocks can be split into measures of extrinsic age (quite variable across immune cell types) versus intrinsic age (not so variable). The intrinsic age clock may be measuring the proportion of senescent cells in immune populations, but this has yet to be robustly demonstrated.

Lou Hawthorne of NaNotics works on targeting the soluble proteome for selective clearance. Nanots are engineered nanoscale sponges that can bind and soak up specific soluble proteins outside cells only, and are then cleared from the body by macrophages. Nanot binding represents an improvement over antibody approaches, both in specificity and in controlling the degree of depletion. The company can engineer nanots to, in principle, bind near any soluble protein. The initial clinical focus is on clearing soluble forms of TNF and TNF receptor (TNF-R1 and TNF-R2), as well as various interleukins to inhibit runaway inflammation. Inflammatory autoimmune conditions and cancers are the initial indications. All cancers shed TNF receptor fragments as soluble TNF-R1 and TNF-R2 in order to decoy TNF as a part of their immune suppression strategy. Clearing these decoys helps to make the cancer visible to the immune system. There used to be a clinic that employed apheresis to clear soluble TNF receptor fragments in terminal cancer patients, a treatment that achieved 60% response rates. The hope is that the nanot approach will improve on this. Soluble TNF receptor proteins are an undruggable target, so small molecules can't be used here, as they would interfere in necessary functions mediated by the receptors. NaNotics has also collaborated on clearing soluble PD-L1, showing benefits in models. Beyond cancer, the company works on clearance of soluble TNF to treat multiple sclerosis, as soluble TNF and soluble TNF-R1 both interfere in oligodendrocyte-mediated remyelination. In MS there is too much soluble TNF. In closing, Hawthorne mentioned that the company is now working on a polymer core nanot that will be able to last for a long time in circulation. They would like to use this to treat endothelial barrier dysfunction and inflammaging by clearing out the best-known circulating signal molecules involved in these processes.

Dobri Kiprov of Circulate started with an outline of the recent history of parabiosis research, starting with a collaboration with the Conboys. Further research after that supported the use of therapeutic plasma exchange as an approach to treat aspects of aging, the practical way to implement something like parabiosis in humans. Clinicians can remove plasma and substitute in young plasma, but this can produce side-effects. So they instead use 5% albumin in saline. Albumin comes from donor plasma, where the average age of donors is 25 or so. Kiprov argued for the quality of the albumin to likely be an important factor in the effects of parabiosis, given it has immunomodulatory, anti-inflammatory, and antioxidant effects. He outlined a recent clinical trial of therapeutic plasma exchange, which is double blinded and enrolled 40 patients. There was only one adverse reaction over the course of 360 procedures conducted during the trial. The clinicians assessed hand grip and similar values of physical condition, measures of cognitive function, and senescence-associated secretory phenotype (SASP) proteins in circulation. Treatment resulted in some improvement versus controls in all of these. The company continues to analyze the copious study data. Important goals include answering the question of how long the effects last for, as well as how to identify which patients will respond positively to the therapy.

Alejandro Ocampo of Epiterna spent some of his presentation on a sketch of the incentives shaping the longevity industry. Companies are focused on applying their work to specific age-related diseases rather than to aging; they typically don't even test to see if life span is extended in mice as a result of their treatment. This is because of regulatory concerns, in that trials to assess aging will be very costly, and no-one wants to be first to try to take the TAME trial design and convince the FDA to let them do it. So instead companies aim at regulator approval for one age-related disease followed by off-label use. Ocampo is concerned that this approach will leads to the failure of trials for viable anti-aging therapies that happen to be a poor fit for the chosen disease. Also, founders tend to lose control of the company as it moves forward, and if it starts working on one disease it may never change to focus on life extension; this has already happened. Learning from this, Epiterna tries to deliberately work on longevity rather than disease. The company is focused on aging in dogs, and are working to develop supplement based approaches to slowing aging. Why dogs? Because it is the largest companion animal market and there is a much lower regulatory cost and risk than is the case for human medicine, particularly given recent efforts to make regulators accept aging as an indication in animals. Additionally, dogs have a short enough life span to allow proof of effects on aging with a feasible cost. Why supplements? Because of the faster path to market and lower regulatory hurdles. The company has developed a low-cost screening platform that screens compounds for life extension in numerous short-lived species, working through yeast, worms, filies, killifish, and mice. In one year they can run ~3000 molecules in yeast and narrow down to a final 20 in mice that are consistently extending life across these species. The output of this screening will lead to trials in companion dogs, currently planned to last 2-3 years and include as many as a thousand animals.

Lorna Harries of SENISCA works on reprogramming cells by designing and screening oligonucleotides and small molecules that can suppress detrimental alternative splicing of RNA characteristic of aging and cellular senescence. This is a way to produce senotherapeutics that reprogram senescent cells into behaving better, or possibly even exit the senescent state if they are in early stage senescence. This screening platform can in principle be more selective about what type or stage of senescent cells are targeted than existing senolytic drugs. The SENISCA program originated with the unbiased screening of age-related changes in gene expression in samples from hundreds of people, where the results pointed to the importance of RNA processing pathways and altered expression of splicing factors. The company is developing oligonucleotides as therapeutics to target aging in general, and have a codevelopment partnership to develop small molecules for topical use in skin aging. The researchers have developed their own assays for senescent cell burden in tissues and cell cultures, as well as making it possible to distinguish between early and late senescent cell states. SENISCA is initially focused on idiopathic pulmonary fibrosis (IPF) as an indication, and has shown shown reduced senescence, fibrotic markers, collagen deposition, and DNA damage in human IPF patient cells in vitro following treatment. The company has tested intranasal delivery of naked oligonucleotides in mice, and show delivery to lungs, a promising start.

Stephanie Dainow of Lifespan.io gave, I'm told, an interesting presentation, particularly given that SENS Research Foundation and Lifespan.io are now merging. Unfortunately I had to miss this one. Apologies!

Phil Newman of Longevity.Technology discussed the demographic aging trend as a motivation to work on the treatment of aging as a medical condition, where even a modest slowing of aging could greatly reduce the vast economic cost of ill health in later life. There is a clearly a trend in the science and development, age-slowing, and age-reversing therapies will come into being, and things are going to become very interesting as average life expectancy increases step by step to be far greater than 100 years of age. That future is being built now, but what will it look like, where will the greatest focus fall? We can all speculate, and will all likely be surprised in many ways. Newman moved on to an overview of the present system of medical regulation and reimbursement; how the money flows, the economic incentives for Big Pharma, medical insurance companies, and governments. Chronic disease costs a lot, and therapies to effectively slow or reverse aging will improve the economics for everyone. How long will it be until effective therapies to treat aging exist? This is difficult to predict, but we might be pessimistic when looking at the decades it has taken for some currently popular therapies to move from fundamental research to recognition of value to active clinical development.

Lukas Langenegger of Hemotune showcased their approach to plood purification, improving dialysis techniques to remove specific molecules in blood. As for the NaNotics technology, this offers the ability to selectively remove multiple specific molecules and thus address multiple mechanisms at one time in the case of complex conditions. Hemotune make a machine that allows better, selective blood purification. As in all dialysis, blood runs through the machine. At the core is an exchangeable cartridge of engineered magnetic nanoparticles decorated with antibodies or other binders specific to selected molecules in blood. These nanoparticles, and the molecules newly bound to them, are removed by magnets before blood is returned to the patient. Hemotune is initially targeting sepsis-induced immunosuppression, a lasting condition that follows sepsis, and are working towards a clinical trial to be conducted in a few hundred patients. Secondly, the company has developed a proof of concept for the removal of anti-AAV antibodies. This will in principle enable AAV-based gene therapy to work in patients with existing antibodies. Antibodies prevent repeat dosing, but many patients have preexisting anti-AAV antibodies even prior to a first dose.

Robin Mansukhani of Deciduous Therapeutics presented on their senolytic immunotherapy, a small molecule treatment that produces a lasting alteration in the behavior of invariant natural killer T cells (iNKT cells) to increase their ability to clear senescent cells. iNKT cells coordinate the removal of senescent cells. Explaining the origin of the program, Mansukhani explained that the realization that accumulation of senescent cells is driven by failure of the immune system to clear these cells in a timely fashion led to research aimed at identifying which immune cells were dysfunctional and why. That in turn pointed the way to an intervention to reverse that dysfunction. The animal data generated by Deciduous demonstrates the effective lasting clearance of senescent cells, and a consequent sizable reduction in fibrosis in mouse models of idiopathic pulmonary fibrosis, a far greater effect than is produced by the current standard of care treatment of nintedanib. The company has also shown improvement in type 2 diabetes mouse models. In general, an effective senolytic should have a large value, as it can be applied to near every age-related disease in some way. The next steps for Deciduous are to scale up manufacturing processes and conduct IND-enabling studies. They are also looking into how to replicate the iNKT intervention in the brain, where the immune system is isolated and different, and would thus require identifying a different cell population and form of dysfunction to correct.

Matthew O'Connor of Cyclarity showed a sampling of studies demonstrating that 7-ketocholesterol, a harmful altered form of cholesterol, is associated with cardiovascular disease. At the SENS Research Foundation the staff spent some time looking into how to clear this molecule, and settled on a cyclodextrin based approach - finding ways to adapt existing cholesterol-binding cyclodextrins to only bind 7-ketocholesterol. In the process they produced a platform for cyclodextrin design that might be applied to other goals. Cyclodextrins have many uses, and existing cyclodextrin drugs bind various unwanted molecules to remove them from the body. The industry has a lot of experience in working with them. Cyclarity has shown in vitro that their cyclodrextrin drug can restore function in macrophages induced by 7-ketocholesterol to become foam cells. The company is headed to the clinic: the first GMP batch is produced, and a phase 1 safety trial in healthy volunteers and a smaller number of patients with plaque is set to start this year in Australia.

I presented on our work at Repair Biotechnologies, starting with a brief tour of the data showing that the risk of cardiovascular disease and mortality via stroke and heart attack rises with the burden of atherosclerotic plaque present in the arteries. For example, a Dutch study showed that 5-6 arterial plaques identified by imaging indicates a five-fold increase in risk over those with no visible plaques. The lipid-lowering standard of care (meaning long-term treatment with statins, PCSK9 inhibitors, and the like) does not meaningfully reduce plaque size, however. As little as a 1% reduction in plaque volume leads to a ~20% reduction in stroke and heart attack, but only a fraction of patients can achieve even this much plaque reduction after a year or more of treatment. The average improvement is close to zero. In comparison, the Repair Biotechnologies LNP-mRNA gene therapy can produce a 17% reduction in aortic plaque volume after six weeks of treatment in the LDLR knockout mouse model of accelerated atherosclerosis. Additionally, the therapy removes plaque lipids and encourages plaque stability in the APOE knockout mouse model of atherosclerosis. This therapy works by clearing a toxic excess of free cholesterol in the liver, restoring the liver to homeostasis and producing systemic beneficial effects throughout the body. The company is planning a series A round to fund the path to a first clinical trial in the rare genetic condition of homozygous familial hypercholesterolemia in 2026, with a potential fast track approval leading to off-label use for severe atherosclerosis in the general population.

Brian Kennedy of the National University of Singapore (NUS) opened his presentation with a complaint about the lack of preventitive treatment taking place in the period of healthy life. We have a sickcare system that focuses only the part of life when people are demonstrably unwell. Doing nothing while people are healthy is in fact causing harm, because aging is still progressing towards sickness while people are ostensibly healthy. The programs at NUS focus on the interface between biomarkers and interventions. One example of their work is a broad set of combinatorial studies, in which it was shown that the combination of any two supplements or small molecules that are modestly good on their own can produce any sort of result, bad or good, often bad, and no-one can yet predict in advance what the outcome will be. The NUS researchers conduct various simple interventions in mice while assessing life span and biomarkers, attempting to be rigorous in setting up a cost-effective system to better evaluate the effects of these interventions. Kennedy went on to make the point that we don't know much about widely used medical tourism treatments, meaning stem cell therapies, exosomes, and so forth, and he wants to work with clinics in order to gather data on the outcomes in people undergoing these studies - a matter of using rich people as model organisms, as he said. He also made the point that older people who are in a worse state of health, with an accelerated biological age relative to chronological age, appear to respond better to some interventions. He offered the example of a human alpha-ketoglutarate (AKG) study in supplement users (lacking a control group) in which epigenetic age was reduced. It is unknown as to whether a better relative outcome in less healthy individuals is the case for all interventions. The NUS researchers are repeating this AKG study with a control group, and should have results in 2025. Kennedy noted that AKG delays fertility decline in mice, and speculated on whether this could be a general effect across many interventions, because mechanisms that slow aging should have evolved to specifically slow reproductive aging, while everything else is a side-effect of that outcome. Moving on to aging clocks, the NUS team has produced a metabolomic aging clock, and along the way demonstrated that AKG levels in circulation decline with age. The researchers are also working on several other different clocks built out of combinations of clinical parameters, similar to phenotypic age and using data from the NHANES study, on the grounds that a clock of this nature should produce results that are more directly comprehensible and useful to clinicians.

Alexander Leutner of Cellbricks outlined their approach to tissue engineering. The company has developed a light-based bioprinting process. Laser light is projected into into a dish of bioink, each pulse of light making a tiny volume of the ink solidify. In this way the researchers can construct complex structures layer by layer: build a layer, raise it out of the bioink, build the next layer, and so forth. They can produce vascularized blocks of tissue in this way, and have manufactured functional cartilage, liver, pancreas, breast tissue, and others. They can also create tumor models or other forms of diseased tissue. The company aims to create implantable blocks for reconstructive surgery, such as following breast surgery, or tissue resections to remove tumors, or to restore function in aged livers by implanting a patch of functional liver tissue. The company has conducted a great deal of work to demonstrate that their tissue blocks are functional and stable over time, and match the strutural properties of native tissue as much as possible. They are presently conducting tests in animal models, and working towards partnerships with large pharma companies, which seems to be the standard approach for tissue engineering companies.

Matthew Scholz of Oisin Biotechnologies discussed their platform for genetic medicine based on LNP-mediated DNA delivery. At this point their first indications are sarcopenia and frailty, accumulation of unwanted fat, and accumulation of senescent cells. The company started with a focus on senescent cells, but that was not much discussed in this presentation, as Oisin obtained more support, funding, and interest for the other indications. The platform for delivery is the Entos Pharmaceuticals fusogenic LNPs, lipid nanoparticles that use a fusion protein derived from a virus to enable cell entry directly into the cytoplasm. This is distinct from the usual LNP path of endocytosis into a membrane-wrapped vesicle that must then be escaped to enter the cytoplasm. Fusogenic LNPs have no cell preference, and will enter any cell they encounter. This can be used as a starting point to build versions with some selectivity, but the unmodified LNP is the closest anyone has come to a vector that has broad body-wide distribution without the major organs taking up most of it. The company uses DNA machinery as a cargo for the LNP to engineer very selective expression of transgenes in specific tissues. The first application is to upregulate follistatin in to produce muscle growth. The team has demonstrated this outcome in mice, including in very old mice. The second application is to destroy unwanted fat cells, and the technology can selectively target specific fat pads via promoters that are only active in those tissues. They can also change the fusogenic LNP to more selectively target fat cells specifically. In effect the result is liposuction without surgery. In the future Oisin wants to broaden this technology platform to many other potential uses. The company is presently raising an A round led by Abbvie Ventures.

Jean Hebert of BE Therapeutics presented on tissue engineering for the brain. Permanent brain damage is a problem in many contexts, such as aging, injury, and cancer, and there is no approach at present to replace that tissue. The company is trying to develop a way to regrow brain tissue based on the recreation of developmental processes. Starting with the neocortex, the team analyzed precursor cells, and can now assemble an architecturally correct, vascularized neocortex organoid prototype from cell populations derived from induced pluripotent stem cells. The neocortex is a very dynamic part of the brain, with connections and usage changing constantly, so it seems possible to put in new tissue and have it be used appropriately to encode information. The team has implanted prototype tissues in mice, replacing a part of the neocortex that was surgically removed. They are now proceeding with work on human tissues, testing the function of developing neurons in preparation to optimize the form and function of the prototype tissues. The initially targeted indications involve damage to the neocortex, such as that resulting from stroke and dementia. The company is in the early preclinical stage, and has yet to conduct studies in animal models of those conditions.

Janine Sengstack of Junevity talked about the platform that she developed during her PhD, enabling discovery of transcription factors that alter cell behavior into more youthful phenotypes. Gene expression changes with age, the large number of individual changes can be mapped and measured, and thus one can screen and identify transcription factors that affect a large faction of this network of genes. The company uses siRNA to downregulate specific transcription factor expression, and have demonstrated proof of principle in vitro for liver cells. The treatment improved cell function along with resetting some of the map of changed gene expression. The team has used the platform to determine candidate transcription factors to suppress in the aging liver and fat tissue, and are working on skin aging as well. They are collaborating with a pharma company for target discovery in obesity. They have shown improved liver function, improved mitochondrial function, and lowered liver fat in obese mice using siRNA suppression of one transcription factor candidate. In skin, they have found a way to improve collagen production and restore more youthful gene expression across thousands of genes via siRNA suppression of a single transcription factor.

Joanna Bensz of Longevity Center Europe, Petr Sramek of the Healthy Longevity Clinic and LongevityTech.fund and Elisabeth Roider of the AYUN Health & Longevity Center presented on their respective longevity clinics. The most interesting of these projects, the one that isn't just a provision of boutique medical services, is the Healthy Longevity Clinic. This group are trying something new, a fusion of investing in companies, giving those companies a path to clinical trials outside the US, and clinics to offer services that will eventually include new therapies created by portfolio companies. They have established a number of clinics, in Praque and Florida, with a subsidiary in the Bahamas set up to conduct clinical trials there. Medical development is slow, and so it will take some time to see whether this proves to be a viable and helpful approach in practice: it would require a sizable fraction of companies to step away from the present well-beaten and thus safe path with regulators.

A panel of investors discussed the industry: Jens Eckstein of the Hevolution Foundation; Jan Adams of Apollo Health Ventures; Sergey Jakimov of LongeVC; Marc P. Bernegger of the company builder maximon; Alex Colville of age1; Patrick Burgermeister of Kizoo Technology Capital. The group offered a considerable diversity of opinions on what is important in the field. A lesson to take away is that the natural size of a faction of investors is one investor; they are all quite different.

Jürgen Reeß of Mogling Bio talked on the development of new, recently patented CDC42 inhibitors based on CASIN, a molecule that has been used to demonstrate reversal of stem cell aging and improved immune function in mice. The team sees CASIN as having too low a bioavailability to be a viable drug, too much of it is needed per dose. The new CDC42 inhibitors have similar effects, but with lower doses. The team has shown that CDC42 inhibition with CASIN can slow tumor growth in mouse models to the same degree as a PD1 checkpoint inhibitor, and the data suggests that this is an immunomodulatory effect achieved via altered regulatory T cell behavior. If combining CASIN and a PD1 inhibitor, tumors shrink and vanish in a mouse model. Thus cancer will be the company's first indication. The company is working towards IND-enabling studies in 2025, and are meanwhile running a number of collaboration programs to broaden the set of possible indications with proof of concept data.

Aaron Cravens of Revel Pharmaceuticals put advanced glycation end-products (AGEs) such as carboxymethylysine (CML) and glucosepane cross-links into the contxt of a damage-based view of aging. Aging is accumulated molecule damage, and repairing that damage is rejuvenation. AGEs are known to contribute to many aspects of aging, and Revel develops a platform to discover enzymes that can break down specific AGEs. Going into detail on the present programs, CML exists in a free circulating form and a bound form in the extracellular matrix, both of which provoke inflammatory reactions. In the last few years the company has developed enzymes that are much more effective than the initial 2019 candidates when it comes to clearing free CML. Cravens sees success with free CML as a stepping stone to the harder task of success with bound CML in the extracellular matrix. The company has considered which AGEs offer the fastest to get to the clinic; while the Revel started with a focus on glucosepane, it is a harder prospect. CML is less challenging, and this is now an initial focus. In principle, an early success with CML will build momentum for further investment for work on the more challenging AGEs.

Aaron Friedman of Reservoir Neuroscience started his presentation by noting that aging is complex and brain aging is particularly complex. Yet the research and development mainstream has ignored this complexity in favor of a relentless focus on just a few things, as in the case of amyloid and Alzheimer's disease. He suggested that the evidence suggests that Alzheimer's is largely a lifestyle disease, and thus interventions derived from lifestyle factors can postpone or slow Alzheimer's. In particlar, people who exercise have a 45% reduction in Alzheimer's risk, somewhat better than the effects of current anti-amyloid antibody treatments. Additionally, imaging data shows that loss of vascular health is the largest factor contributing to Alzheimer's; vascular aging appears before the increase in amyloid burden, and is a larger and easier signal to detect. Thus the industry should be focused on treating poor vascular health. The company intends to develop drugs that target this vascular dysfunction, and has built a drug discovery platform using organ-on-a-chip screening in blood vessel organoids. The team is in the early stages of lead optimization for one candidate inhibitor of the prostaglandin E2 receptor 2 (EP2), which is upregulated in aged and damaged blood vessels. This is a master regulator of inflammatory responses, and so suppressing it effectively should reduce chronic inflammation. Friedman notes that the beneficial effect of long-term NSAID use (specifically ibuprofen in the study referenced) on Alzheimer's risk may be mediated by indirect inhibition of EP2.

Chris Bradley of MatterBio works on advanced sequencing. There are many genomes in the body, as every cell is a little different, genetically and epigenetically. Unrepaired DNA damage accumulates constantly. Most of this is neither good nor bad, it is just noise that increases with age. Researchers think that the greater the mutational burden, the bigger the impact on aging. Speed of mutation accumulation is correlated with species life span, and regardless of species life span every cell has 1000 to 5000 mutations in old age. One consequence of mutational damage is cancer. The MatterBio plan is to (a) read the DNA, (b) identify mutations, then (c) either reverse mutations directly or replace bad cells. The team has developed a novel approach to next generation sequencing in order to see single cell mutations; this is a commercial technology being sold now. They are designing DNA editing machinery that can fix a mutation, and this is still a very early stage project. Lastly, the team has engineered bacteria and markers that allow the destruction of mutated cells, and this is heading into to the clinic as a treatment for cancer. They have shown both pancreatic cancer and ovarian cancer reduction in metastatic preclinical mouse studies.

Nikolina Lauc of GlycanAge discussed the company's aging clock based on measures of changing glycan levels. Glycosylation is a posttranslational modification that produces glycans. Immunoglobulin G glycans are among those that change significantly with age. Few labs work with glycans, but this group has at this point generated more than 160,000 glycomes from human samples. Interestingly, glycan changes can indicate early signs of later chronic disease up to a decade in advance for many conditions, including hypertension and autoimmune conditions. The GlycanAge clock compares well with the best epigenetic clocks in predication power for mortality, but the accelerations are different for age measured by glycans versus age measured by epigenetic changes. A few interesting differences are noted: GlycanAge shows that metformin has no effect on aging, while professional athletes have poor GlycanAge measures in comparison to those who undertake only moderate exercise.

Sophie Chabloz of AVEA presented on their development of a collegen precursor for skin aging. This has all of the slick marketing appearance of a very standard skin anti-aging company at the less reputable end of the industry, but they do at least have an interesting scientific program under all of that cover. After noting the existing industry strategies for adding collagen to skin and diet, and the drawbacks, Chabloz discussed the company's development program. Work started in in C. elegans before moving to cell models of skin. The company has tested their collagen precursor in combination with alpha-ketoglutarate in C. elegans, showing a modest extension of life span.

The last panel of the conference was led by Nina Ruge, a science journalist and author. I was on that panel with (in no particular order) Eric Verdin of the Buck Institute, Brian Kennedy of the National University of Singapore, and Phil Newman of Longevity.Technology. We talked about longevity clinics and what they can offer to the industry; to my mind the most interesting thing that clinics can do for us all is to free up their data and help organize clinical trials. Ruge asked us our opinions on the most interesting part of the industry, and we all had radically different answers on that topic, just as we differed on where we would invest funds for the best outcome, given the power to do so. It is characteristic of the aging and longevity field that almost everyone is in their own group of one when it comes to what the next steps should be.

It remains to be seen as to when the next conference in this series will be held - probably in 2026. I recommend attending. This remains an event at the core of the longevity industry. Many of the most interesting presenting founders and attendees have been involved in some way since the start of this great endeavor. Many of the presentations offered a strong identification with the Strategies for Engineered Negligible Senescence (SENS) viewpoint of aging as accumulated cell and tissue damage, and thus damage repair is the way to treat aging. Consider adding the next Rejuvenation Startup Summit to your calendar when it is announced.