Fight Aging!

A fair number of longevity industry and related companies presented this past weekend in Berlin, at the Rejuvenation Startup Summit hosted by the Forever Healthy Foundation. Unlike the past Undoing Aging events, this is much more focused on the industry rather than on scientific programs, but there was nonetheless a great deal of science on display. I took a few notes in between other activities, for posterity. As Michael Greve noted in his introduction to the participants, these are the early years of what will become the largest industry on the planet. Everyone ages, and everyone is a customer for the rejuvenation therapies and related technologies that lie just around the corner.

Eric Verdin of the Buck Institute gave the opening keynote, discussing recent work on biomarkers of aging, and specifically the most promising line of epigenetic clocks based on assessment of DNA methylation status. Given ways to reliably extend life in mice (e.g. rapamycin and senolytics), we now need a way to measure that outcome that doesn't involve waiting around for the results of a life span study. The point made in this presentation was that different immune cell populations exhibit sizable differences in assessed epigenetic age, which probably means that all clock data based on blood samples is suspect. The Buck Institute researchers have found differences of as much as ~20 years in epigenetic age between immune cell types, as well as differences based on infection and inflammation status, so clearly more care needs to be taken here. In an attempt to address this issue, the team built a new clock that is invariant across immune cell subpopulations. We will no doubt be hearing more about this as it progresses, given the prevalence of work that uses epigenetic age derived from blood samples.

Lou Hawthorne of Nanotics gave an outline of their technology platform, a way to produce particles that bind specific molecules in the blood stream in a controllable way, depleting them for minutes to hours. Heterochronic parabiosis research has led to evidence for harmful factors to circulate in the aged bloodstream, maintaining inflammation and dysfunction, which naturally leads to the desire to remove these factors in a targeted way. Nanotics is particularly focused on pro-inflammatory factors, and their view of aging is inflammation-centric. Thus the cytokine storm of sepsis is not a bad starting place to test this sort of therapy in the clinic. The Nanotics platform allows the targeting of signal processes that are inaccessible to small molecule therapeutics, so offers ways to potentially dial down inflammatory signaling without also blocking necessary immune functions.

Alexander Schueller of cellvie discussed their view of the mitochondrial dysfunction observed in aging, and the relevance of mitochondrial damage caused by ischemia to the cell death and dysfunction following ischemic injury. The cellvie approach is to deliver replacement mitochondria to be taken up by cells in need. Like the other companies working on this approach, they are near entirely focused on the logistics and process development needed for this goal. Their intent to is to generate allogeneic mitochondria, harvested from standard cell lines. Once ready, cellvie is looking at sarcopenia as a first indication for clinical development, based on promising animal data.

Vlad Vitoc of Maia Biotechnology gave an impressive overview of their progress towards a near-universal cancer therapy. They develop therapies based delivery of THIO, a compound that is metabolised and utilized by telomerase, and then incorporated into telomeres to produce cell death. Since near all cancer cells aggressively utilize telomerase, these are the cells that die when THIO is introduced. The company has orphan drug designations for a variety of cancers, and are well advanced in the path to clinical trials. A first phase 1 is running now, with further trials coming up in next few years, including one phase 2 just starting in Australia. These trials are conducted in partnership with Regeneron, and they put THIO into patients in conjunction with a Regeneron-developed checkpoint inhibitor therapy. The company went public recently, and they are using the sizable funding they have raised to date in order to build new and more efficient versions of THIO. We should expect the important questions regarding telomerase as a target to be answered in the years ahead, now that it is an ongoing project, such as how to manage the effects of telomerase-targeted therapeutics on stem cell function, and what those effects are in practice.

Chris Rinsch of Amazentis talked about the use of urolithin A as supplement-based approach to improving mitochondrial function in aged individuals. Their initial aim is to look at muscle function in aging, attempting to produce modest improvements via this approach. They hold the consensus view that urolithin A works by improving both mitophagy and mitochondrial biosynthesis, though as for many such compounds exactly how it achieves this outcome is far from settled.

Unfortunately, I had to miss the presentation by Alex Blyth of LifT Biosciences. This company pursues an interesting approach to cancer via transplantation of donor leukocytes; you might recall the original work on granulocyte transfer presented at SENS meetings back in the day. The original research showed great promise, and the company has been doing well these past few years, judging from the public updates.

Dobri Kiprov of Lyfspn presented on the merits of therapeutic plasma exchange. He presented a range of human data from patients in past years, including a reduction of epigenetic age via this approach, as well as immune improvements, improvement in joint issues, and improved liver and kidney function. Their view is that the most important aspect of this removal of bad factors is that it modulates the immune system, reducing the state of inflammaging and consequent harm and dysfunction. But the data they have is not rigorous, it results from clinical practice, and thus they founded this company to generate high quality data via clinical trials. They acknowledge that these are still the early days for therapeutic plasma exchange, and they still lack firm, defensible answers to even simple questions such as how long the benefits last from one treatment.

Pankaj Kapahi of Juvify discussed the science supporting this supplement company spinout from the Buck Institute. Their product is a modulator of glycation, acting to reducing the impact of sugar consumption and obesity on long-term health. Their hypothesis is that the generation of advanced glycation endproducts (AGEs) is the major problem that is produced by sugar metabolism. They work with compounds that target one type of shorter-lived AGE, methylglycoxal AGEs. Thus benefits may be a matter of reducing inflammatory signaling caused by AGEs via the RAGE pathway, but they think that RAGE is not the only mechanism of interest here. Interestingly, these compounds suppress appetite, so somehow short-lived AGEs are acting as appetite enhancers. Ongoing studies in mice also indicate that this interference in short-lived AGEs, conducted over the long term, decreases growth hormone signaling and reduces the burden of cellular senescence, among other benefits. Since appetite is reduced, is it possible that the benefits are all simply benefits of calorie restriction? They think that this is a factor, but only part of story.

Yuri Deigin of Youth Bio presented on partial reprogramming, a huge potential market, based on evidence from animal studies showing rejuvenation in many different tissues. Certainly, investors believe it will be huge, judging by the vast financial support for this part of the industry, dwarfing investment elsewhere. Youth Bio are an early stage preclinical company, at the point of having completed mouse studies showing reversal of measures of aging. They are working on a few different projects in parallel. Firstly they are attempting to produce new reprogramming approaches with novel factors and tissue-specificity. They avoid the liver and intestine for safety reasons, as mice tend to die when these are repeatedly reprogrammed. Secondly, they are working towards viable therapies based on use of the existing OSKM factors. Alzheimer's disease is their first indication on this side of the house, and they propose the use of a one-time gene therapy that introduces inducible genes, followed by delivery of small molecules for periodic activation of those genes.

Silke Hüttner of Rejuvenate Biomed outlined their approach to combinatorial therapies using small molecules identified through screening and later optimization. They are, unfortunately, cagey about the details of their compounds, but their present lead therapeutic candidate is a combination of two compounds that they have developed, which positively affects inflammation and other properties relevant to aging. The company is initially focused on sarcopenia, but they want to move on from there to other age-related conditions and then aging itself as a target. The company has produced successful studies in both progeroid mice and naturally aged mice, with early human trials ongoing.

Mourad Topors presented as the CSO of Repair Biotechnologies, the company that I co-founded with Bill Cherman. We develop a means of safely breaking down excess intracellular free cholesterol, delivered as a gene therapy to arbitrary cells in the body, or as a cell therapy of engineered cells equipped with this capability. We work towards reversal of atherosclerosis, the primary cause of human mortality, resulting at root from the presence of excessive cholesterol deposits in arterial walls. We are finding a faster path to the clinic in treatment of nonalcoholic steatohepatitis (NASH), however, largely because the delivery systems for liver-targeted gene therapies are far more developed. We presented recent results showing reversal of liver inflammation and fibrosis in NASH model mice, and noted that we're raising funds to start our clinical development program leading to human trials. Therapies to reverse atherosclerosis progression will follow shortly on the heels of this work on NASH.

Robin Mansukhani of Deciduous Therapeutics discussed their approach to immune system modulation via small molecules, training invariant natural killer cells to attack senescent cells. The point was made that engaging the immune system may be a way to work around many of the present unknowns regarding senescent cell status, biomarkers, and subtypes. Interestingly, a one-time treatment via their approach rouses immune cells for at least months thereafter, consistently clearing senescent cells over that time.

Mike Kope of Cyclarity presented on their approach. Cyclarity is the renamed Underdog Pharmaceuticals, a spinout from the SENS Research Foundation that employs engineered cyclodextrins to bind 7-ketocholesterol. This is essentially a test of the degree to which 7-ketocholesterol is a meaningful cause of pathology in human atherosclerosis and other conditions. They have great cell data, showing that they can reverse the foam cell state that arises from 7-ketocholesterol exposure, and they also test in human plaques obtained from cadavers and surgical procedures. Despite a lack of animal models for 7-ketocholesterol presence in atherosclerotic disease, Clarity has engineered a fast path to the clinic, based on the safety profile of cyclodextrins as a class. They will begin their first clinical trials next year.

Cristiana Banila of Mitra Bio discussed the need for better ways to measure skin aging. They have developed a way to measure epigenetic age in skin non-invasively, with no biopsy. They obtain cells from the skin surface via adhesive tape and have shown that this produces the same results as are obtained using biopsies. The company uses this approach to assess methods that are alleged to reverse skin aging, and presented data for an example treatment that can in fact reverse epigenetic age in UV-damaged skin. They plan to test many more of the established and potential skin-focused interventions that exist, to generate personalized recommendations for patients.

Brian Kennedy talked about his scientific work at the National University of Singapore. This spans a range of preclinical studies, including efforts to produce treatments based on the hallmarks of aging and work on biomarkers and epigenetic clocks. They tend to run 6-9 month interventions in mice, starting at 18 months of age, and assessing frailty and biomarkers of aging rather than using life span as a measure of success. Similarly, they run human studies, presently small ones, and again 6-9 months of intervention in healthy older people, while assessing biomarkers. The researchers are focused on the standard panoply of well-known small molecule geroprotectors, such as rapamycin, largely calorie restriction mimetics. In nematode worms, the development of automation now allows this research group to run studies of combinations of such compounds, tens of thousands of these studies every year; this capacity has led to a new company that intends to ramp up to millions of studies or more per year. One of the more interesting conclusions from the work carried out to date is that combinations produce unexpected results. The individual outcome of two small molecules is no guide as whether the combination will be better, worse, or indifferent. Any and all polypharmacy, or even combination of supplements, is a walk in the dark.

Chris Shepard of Thymofox gave an overview of the importance of thymic involution to the aging of the immune function. The insight leading to the creation of this company is that a young thymus regenerates from injury, but this capacity is much reduced in adults, and further so with aging. They are looking for the regulators of this decline, upstream of FOXN1. They aim to produce small molecules to indirectly upregulate FOXN1 expression in the thymus, searching via a high-throughput screen they they designed. They believe that along the way so far they have discovered some genetic regulators of FOXN1 level that may be useful in other ways, but details on their progress to date are light.

Mark Allen of Elevian gave his outline on their work on GDF11, one of the first candidate factors for the effects of parabiosis, back when it was though that the effects of parabiosis might be mediated by beneficial factors in young blood, rather than a dilution of harmful factors in old blood. This line of research has been underway for a while now, and they are narrowed down to applications in stroke recovery as the first clinical indication. Their evidence in mice shows recombinant GDF11 to promote vascular regeneration, activate various stem cell and progenitor cell populations, suppress inflammatory to some degree, and improves metabolism. They think that indications could be addressed via GDF11 therapies, and the first clinical trial for stroke recovery will begin in 2023. Further, they have identified an regulatory responsible for the age-related downregulation of GDF11 expression, and are working towards an antibody therapy as an alternative to delivery of recombinant GDF11.

Matthias Breugelmans of Elastrin Therapeutics discussed the regeneration of damaged elastin fibers in the extracellular matrix to restore elasticity in aged tissues. The company employs an albumin nanoparticle decorated with antibodies that bind to damaged elastin to deliver their therapy in a very targeted way. The nanoparticle contains EDTA and a proprietary PGG compound. In their eyes, damaged elastin in blood vessels and other tissues produces a local inflammatory response which in turn provokes calcification and other woes. They are targeting a variety of indications, including vascular calcification, aneurysm, hypertension, and a few rare orphan conditions. The company has obtained large reductions of vascular calcification in animal models, and a first phase 1 trial starts in 2023. Beyond the nanoparticle approach, they are working with delivery of mRNA encoding tropoelastin in order to stimulate the production of new elastin, but this is quite new, and earlier in development.

Matthew Rosen of CoRegen outlined a regulatory T-cell (Treg) based approach to defeating many different types of cancer. This is a spin out from Baylor College of Medicine, and uses the college infrastructure. One of the ways in which solid tumors subvert the immune system is to co-opt Treg cells, which then prevent other immune cells from attacking the cancer. Researchers have seen that gene knockdown of SRC-3 in Tregs will stop this from happening, however, and the CoRegen therapy is based on this finding. SRC-3 controls a lot of other genes, including checkpoint inhibitors, and it is thus fair to say it is a master regulator of immune capabilities against cancer. The company engineers Tregs by knocking out SRC-3, and then injects those cells, either systemically or into a tumor. This appears to provide lasting benefits in terms of resistance to cancer, and complete remission of existing cancer in mice: a small number of engineered Tregs outweighs the effects of native Tregs. The company is aiming at a first phase 1 in 2023.

Peter Fedichev of Gero presented on the company's use of AI and animal models to characterize the split of degenerative aging into two quite different processes, which they term (a) damage (or frailty) and (b) loss of resilience. These are two quite different things, and the balance between these portions of aging is different in mice and humans. Humans are more resilient, meaning a greater resistance to perturbations to equilibrium in later life. In the Gero view, the hallmarks of aging are all linked, and a drug working on any one will have effects on all. They predict that most small molecules that slow aging in mice will have little effect on aging in healthy humans, because humans are already resilient in ways that mice are not. The company is running drug discovery programs based on this philosophy, and beginning to collaborate with big pharma entities.

Aaron Cravens of Revel Pharmaceuticals presented the company as developing a platform to produce enzyme therapies generally, at a fraction of the cost and time of past efforts. High throughput enzyme engineering, in essence. They use computational modelling of enzyme libraries to suggest new variants and desired properties, then validate in vitro. You will recall that they launched to work on enzymes to break glucosepane, CML, and other cross-links involved in aging, and that remains the initial application of their platform. This is an early stage effort, and they have not yet tested candidate molecules in animals. They intend to raise a series A next year.

Hans S. Keirstead outlined work under way at Immunis, one of the more advanced of the companies presenting at the event. They harvest the secretome of carefully tailored progenitor cell lines, and package those molecules as a therapeutic product. The result contains factors that can modulate the immune system, as well as provide other useful effects on cell behavior. This program is fairly advanced in its progression through the IND process with the FDA. They have demonstrated in IND-enabling studies that delivery of this secretome as a therapeutic helps with sarcopenia and fibrosis, reduces inflammation and arterial stiffness, and improves adaptive immunity. A phase 2 human trial for muscle atrophy is starting up now.

Robert Cargill of Glionics presented work on the use of engineered microglia to deliver therapeutic molecules throughout the brain. It is otherwise hard to get many types of compound into the brain, with good biodistribution, because of the blood-brain barrier. But microglia will naturally spread throughout the brain, provided that native microglia are cleared via some form of CSF1R inhibitor. The company is starting with klotho as the therapeutic molecule of choice. They have demonstrated repopulation following clearance in mice. Just a few thousand microglia will replicate and move throughout the brain, delivering a factor as they go, BDNF in that case. The intent is to generate therapeutic microglia from universal iPSC lines, a popular choice in research and development at the moment.

Rob Konrad Maciejewski of Biolytica outlined a vision for data-driven approach to personalized medicine and lifestyle changes. This is a software company; they build a visualization product for complex health data in order to help patients understand tests, make choices, aim towards goals, and navigate the sizable amount of data that can be obtained these. Then on top of that add recommendations for lifestyle and supplement choices, and managing relationships with doctors and providers. The initial aim is to help people who could in principle make sizable gains in long-term health via lifestyle changes to make use of the present medical assay environment in order to achieve those gains.

Joshua McClure of Maxwell Biosciences presented on their drug discovery platform, based on producing variations on an antimicrobial peptide that is effective against pathogens of many types, including fungi, bacteria, and viruses. The story started with examination of blood plasma from young and old mice, finding a heat shock protein LL-37, a protein that is also an antimicrobial peptide that (a) seems to have broadly beneficial effects on many systems and (b) is downregulated with age. It attacks many targets from cancers to pathogens, acting via membrane disruption. Unfortunately it can't be used as a drug, as is rapidly cleared from circulation, so instead the company makes similar peptides that have the same function while also being stable. This can be, in principle, a replacement for existing antibiotics and antivirals, with additional beneficial effects to health via heat shock protein mechanisms. The company is quite well advanced in their preclinical program, and intends to raise sizable amounts for clinical development in the coming year.

Sophie Chabloz presented on Avea, a standard issue modern dietary supplement company. They presently offer formulations incorporating nicotinamide mononucleotide and the like, aiming to produce NAD+ upregulation.

Felix Frueh of PAGE Therapeutics discussed the value of targeting metastasis in cancer therapy. Prevention of metastasis would make solid tumors far less dangerous, in any cancer. The company pursues an interesting mechanism: cancers produce circulating tumor cells, but only clusters of these circulating cells actually produce metastasis, not single cells. So why not dissolve the clusters? They found an existing drug that achieves this outcome and blocks metastasis in mice. This can then be combined with other cancer therapeutics. A trial in breast cancer patients is ongoing as a proof of concept. Despite all of this backstory from academia, they are actually in quite an early stage as a company, working to produce novel small molecule drugs targeting this cancer cell clustering mechanism via screening.

Jürgen Reeß of the very early stage company Mogling Bio introduced their work aimed at restoration of immune function in older individuals. They wish to use derivatives of CASIN to inhibit CDC42, shown in academic work to rejuvenate the immune system with a single treatment. CASIN appears to improve function in stem cell populations generally, but in the case of hematopoietic stem cells this leads to an improved, more youthful production of immune cells. The company is just getting starting, based on promising mouse data, and will target the obvious indications relating to age-related immune dysfunction.

All told, it was quite an interesting selection of ongoing work. The cancer side of the house in particular is looking very promising these days, with numerous quite general approaches under development that should be both effective and applicable to many different types of cancer.