The Longevity Summit at the Buck Institute, a relatively short two-day geroscience and longevity biotech conference held on December 6-7, was nevertheless densely packed with new research – to the point where we can only cover some of the talks here. The conference was organized by Longevity SF, a nonprofit organization founded by Christin Glorioso, an MIT-trained physician and scientist who is also a co-founder and CEO of NeuroAge Therapeutics.
Held this year for the first time, the Summit is envisioned as Longevity SF’s annual finale event. In line with our strategy of facilitating networking and information exchange in the longevity field, Lifespan.io became one of the Summit’s sponsors.
Buck Institute for Research on Aging in Novato, CA has been at the forefront of geroscience since 1999. Located on a green hilltop with breathtaking views of the valley below, away from noisy neighborhoods and roads, it looks like either a scientist’s paradise or a secluded research facility for a super-spy to infiltrate in an action movie. It turned out to be an excellent place for scientific talks.
T cells and epigenetic aging
The event opened with a lecture by Buck director Dr. Eric Verdin, who presented some fascinating new research fresh out of the institute’s labs. Dr. Verdin’s talk touched on one of the most important topics in today’s geroscience: finding reliable biomarkers of aging. According to Verdin, the perfect biomarker of aging needs to be as versatile as possible, working across tissues and populations. For instance, it must be accurate both in men and in women, which is not trivial, because, as scientists have discovered, the two sexes age differently.
The problem with even the best biological age clocks, Verdin said, is that when blood is used, clocks actually measure the average age of a heterogeneous cell population consisting of as many as 50 different cell types, each with its own pace of aging. The proportions of those cell types in the blood change with age: for instance, the proportion of naïve T cells, which are generally younger, decreases, while the proportion of memory and effector T cells, which are generally older, increases. As a result, T cell differentiation might affect biological age clocks without reflecting “true aging”.
Researchers at Buck devised a new clock that takes this into account. It is as precise as the best epigenetic clocks currently in use while also being insensitive to T cell differentiation; this should make the new clock superior to the current clocks, but it is still in the works, and its performance may improve over time. Interestingly, unlike with other clocks, COVID-19, which alters the T cell population, does not impact the new clock’s acceleration. Verdin also mentioned the famous TRIIM trial in which thymus regeneration led to a considerable epigenetic age reversal. According to Verdin, this could have been at least partially due to shifts in the population of T cells.
Demystifying biological age clocks
The next speaker was Morgan Levine, who is one of the best experts on epigenetic clocks and currently with Altos Labs. Levine described her team’s work on bringing existing epigenetic clocks closer to her definition of the perfect biomarker of aging. Such a biomarker should correlate with chronological age, although not perfectly. It should also serve as an independent predictor of morbidity and mortality, respond to interventions, provide some mechanistic understanding, be reliable with minimal variation in test-retest scores, and, finally, have limited batch effects.
Noisy biomarkers make it harder to detect the effect of an intervention, and traditional clock readings from the same sample can differ by as much as nine years. Levine and her team have developed a method of denoising existing clocks, reducing the variability of results. This also allows scientists to take fewer measurements, which should greatly simplify trials. You can read more about that in our in-depth interview with Morgan.
Another aspect of Levine’s work is to “demystify” existing clocks, which are currently black boxes with scientists having only limited understanding of how they work. The team does this by looking at different tissues and at different clusters or modules of CpGs (genome loci where methylation/demethylation occurs). Levine’s team suspects that different modules might represent different aspects of aging. While research in this direction can help further improve epigenetic clocks, according to Levine, they might never become a perfect biomarker of aging in its entirety.
When proteins misbehave
Dr. Priyanka Joshi, co-founder of NeuroAge, started her presentation by asking the audience whether they believed the amyloid theory of aging. Just like in the longevity community in general, there seemed to be no consensus in the crowd.
Whether or not the theory is correct, it is clear, according to Joshi, that aggregated proteins fail to perform their functions. Aggregation can happen in several stages, which is the case with amyloid beta, and it can be inhibited by small molecules, antibodies, or endogenous metabolites, but the stage at which the molecule intervenes is important. “If we believe in the amyloid process, are we looking at the right species to target?” Joshi asked.
Neuroage is working on a large postmortem cohort of about 2000 brains, analyzing them using various biological age clocks. The main takeaway is that people whose biological age was younger than their chronological age at death, were less likely to have developed Alzheimer’s. Based on this and other insights, NeuroAge has developed a proprietary platform to identify protein products that are specific to slowing brain aging and eventually develop therapeutics against Alzheimer’s and other protein misfolding diseases.
Tissue gentrification is a thing
Sergio Ruiz, CEO of Turn.bio, presented the company’s latest work on CAR T cell rejuvenation, and you can also read about it here. The root cause of chronic disease, he said, was cellular degradation. Young cells renew the cellular environment, removing the need to rejuvenate the entirety of cells. Ruiz jokingly called this phenomenon “gentrification”.
While Turn’s solution based on cellular reprogramming can potentially be used in a wide variety of treatments, the company is currently focusing on the two low-hanging fruits that allow immediate commercialization: immunology and dermatology. CAR T cells are genetically modified cells usually procured from the patient themselves, which means there is already some cellular exhaustion due to age. Turn’s technology can rejuvenate those cells to make them more aggressive in fighting cancer. According to Ruiz, this results in a five-fold increase in proliferation, a four-fold increase in cytotoxicity, and a 75% reduction in the cost of CAR T treatments.
Preliminary trials have shown that treated CAR T cells do not get exhausted even after multiple encounters with the tumor. Ruiz hopes that Turn can begin Phase 1 and 2 clinical trials as early as 2024. He also touted brand-new positive results in skin rejuvenation.
Secretive secreted proteins
A talk by Dr. Hanadie Yousef, CEO and co-founder of Juvena Therapeutics, was impressive starting from the title: “Harnessing the Regenerative Secretome of Human Pluripotent Stem Cells to Rejuvenate Tissues”. Juvena uses a computational platform that combines in silico, in vitro, and in vivo screening to create a proprietary library of secreted proteins with therapeutic potential. Moreover, it employs custom protein engineering for lead optimization. Juvena has 33 hits that can promote rejuvenation of various tissues and one advanced candidate for myotonic dystrophy type 1, a currently incurable muscle degenerative disease.
Juvena is not the only company that has its eyes on signaling molecules, as dysregulation of intercellular communication is one of the hallmarks of aging. Signaling molecules have naturally evolved to be potent and highly selective, which is why Juvena wants to harness their power. Despite their obvious importance, secreted proteins are currently understudied, with no binding partners reported for about 30% of them. To map thousands of secreted proteins to tens of thousands of diseases indications, Juvena uses unbiased quantitative proteomics and machine learning.
Taking on reproductive aging
Jennifer Garrison, assistant professor at Buck, gave a captivating talk on reproductive aging. Ovaries age 3.5 times faster than other organs and are considered geriatric by the age of 35. This peculiar feature of human biology, rarely seen anywhere else in the animal kingdom, gives rise to various health and societal problems. For instance, while women on average live longer than men, their healthspan is shorter. This earlier health deterioration is thought to be linked to menopause. Older age at menopause correlates with life expectancy – not just in women, but also in their brothers, which hints at genetic drivers of aging.
Research into reproductive aging is severely underfunded, but things are beginning to change. Garrison and her team are taking on reproductive aging both inside and outside the laboratory. They are part of the Global Consortium for Reproductive Longevity and Equality (GCRLE), an international organization that brings together scientists and clinicians in a joint effort to fight reproductive aging and educate the public about it. In her talk, Garrison announced the availability of research grants and courses in the field of reproductive aging and touted GCRLE’s white paper on the subject.
The mitochondrial duo
Spring Behrouz and Andy Lee are the founders of Vincere Therapeutics, a Boston-based start-up company focused on mitochondrial dysfunction. They are also husband and wife who began their joint talk with the question, “Who would be amenable to working with their spouse?”, eliciting mixed reactions from the crowd. Judging by their perfectly orchestrated presentation, Spring and Andy get along just fine.
Vincere is working on improving mitophagy, the process of removing dysfunctional mitochondria. One of the diseases associated with mitochondrial dysfunction is Parkinson’s. In the cell, the parkin enzyme tags malfunctioning mitochondria for recycling, but another enzyme, USP30, removes those tags, slowing down the process of mitophagy. Research has shown that parkin overexpression improves mitochondrial health and increases lifespan in animal models. Parkin overexpression and/or USP30 blockade also reduce senescent cell burden in the heart. Vincere aims to create small molecules that would either aid parkin or block USP30, hopefully leading to an improvement in multiple conditions, including Parkinson’s.
What are senescent cells anyway?
Marco Quarta, CEO of Rubedo, gave a talk on senescent cells. He started by calling cellular senescence “poorly understood”, which is true but rather unusual to hear from someone who is trying to make money on this very phenomenon. “As a matter of fact,” Quarta continued, “there is no such thing as senescent cells.” He went on to explain that a cell can be triggered into various states of senescence by different stressors and that these states play completely different roles in various tissues and diseases.
Rubedo, like many companies, employs a proprietary AI-driven platform. Rubedo’s is built around studying various subtypes of senescent cells based on single-cell technologies. The reason is that there are not a lot of senescent cells in tissues, which makes bulk samples noisy. The platform identifies and clusterizes cells with abnormal transcriptional profiles, which enables Rubedo to look for highly specific compounds that only target a well-characterized subtype of pathological cells. As a result, in preliminary trials, one of Rubedo’s prodrugs nearly completely eliminated senescent cells with minimum to no damage to healthy cells.
Dogs and intermittent fasting
University of Washington professor Matt Kaeberlein’s talk at the conference focused on his Dog Aging Project (DAP),which has been in the works for several years and is now moving forward. Kaeberlein reported on the project’s design, stressing that this is an open geroscience project. The data for year 1 is accessible to everyone, which means you can try playing with it to find interesting correlations. In his talk, Kaeberlein encouraged data scientists to do just that. Currently, there are more than 41,000 dogs enrolled in the DAP’s longitudinal arm, but Kaeberlein said that enrollment is far from over.
One of the noteworthy early results that Kaeberlein shared was related to feeding frequency. Preliminary DAP data shows that one meal a day is associated with lower risk across a wide range of diseases. Kidney, gastrointestinal, and liver health seem to benefit the most. Kaeberlein duly noted that these results do not imply causation and are not even longitudinal yet.
The DAP’s experimental arm is Test of Rapamycin in Aging Dogs (TRIAD), which is about to begin properly. However, Kaeberlein shared some data from a small preliminary trial suggesting that rapamycin may improve heart function in dogs. There was no evidence of detrimental side effects, which is good news heading into the main trial. If you want to know what else Matt is up to, read our recent in-depth interview with him (spoiler: it’s worms).
Harnessing the power of evolution
One of the most unusual talks at the conference was given by Ashley Zehnder, co-founder and CEO of FaunaBio, a non-conventional start-up company aimed at harnessing the mechanisms that make some species particularly long-lived. Research into long-lived species has been almost entirely academical. While it has yielded many exciting insights (for more on that, read our review of Methuselah’s Zoo, a book by Steven Austad), it is generally considered too early-stage to be commercialized, which makes FaunaBio an interesting outlier.
FaunaBio has a particular focus on hibernation. This process involves drastic changes in the rate of metabolism, which allows the species of squirrels that FaunaBio is studying to drop their body temperature to a mere 5 degrees Celsius. Amazingly, every few days, those squirrels quickly rewarm themselves before going back to hibernating. These jolts would be extremely harmful to tissues, causing something like a reperfusion injury, but the squirrels have developed mechanisms, such as reactivation of fetal genetic programs, to repair damage. Hibernators are apparently very good at DNA protection, cellular regeneration, and improving mitochondrial function.
FaunaBio is searching for the genes responsible for these amazing feats of evolution in the hope of developing therapeutics for humans, and it has already partnered with the pharma company Novo Nordisk. We will be interviewing Zehnder early next year, so stay tuned.
Encouraging Phase 1 data on muscle atrophy
BioAge is a well-known player in the longevity field. Founded by Kristen Fortney and Eric Morgen, it is a clinical-stage biotech with a portfolio of therapies that target the molecular causes of aging. According to Morgen, who presented at the conference, BioAge’s overarching goal is compression of morbidity, in which people may not necessarily live longer but spend more of their lives in good health. BioAge uses a cohort of more than 10,000 patients to take longitudinal measurements of aging, which helped the company establish mortality hazard ratios for thousands of proteins.
Along the road, the protein apelin caught the company’s attention. Apelin is associated with longevity and muscle strength. BioAge found a discontinued drug with a good safety record that could interact with apelin. This candidate drug rescued muscle atrophy in the limbs of aging mice, and in another experiment, it stopped the age-related decrease in spontaneous mobility and forelimb strength.
Recently, BioAge conducted a Phase 1b human trial in healthy elderly volunteers that were subjected to bed rest for 10 days. The candidate drug significantly prevented muscle atrophy across several endpoints. BioAge will be hosting a virtual event on January 4th to discuss the results of this trial and the design of the upcoming Phase 2 trial.
A talk focused on disparities
Yvonne Dotson and Dr. Stacie Walton, founder of The Diversity Doctor, gave a keynote talk on discrimination faced by African-American women in the healthcare system. On average, they do not live as long as Caucasian women, and racial disparities have been documented in pregnancy-related mortality and disease, cardiovascular disease, obesity, and COVID-19 mortality.
While some of this might be explained by socioeconomic inequality, the reported disparities show that African-American women are undertreated for pain and are less likely to receive hormone replacement therapy after menopause. Walton also talked about her personal encounters with bias and discrimination in healthcare settings and concluded this keynote talk by encouraging the audience to use bias examination tools designed by researchers at Harvard and other universities.
Media and advocacy are getting seen
This was one of the first longevity conferences where the topic of media and advocacy received a proper amount of attention. Lifespan.io was represented by our executive director Stephanie Dainow, marketing expert Jake Mabey, and me, Arkadi Mazin.
As a Lifespan.io staff writer, I had the honor of participating in a panel discussion on the role of media in the longevity field, along with the president and CEO of Foresight Institute Allison Duettman and Chris Patil, VP-Media at BioAge Labs. We talked about the importance of getting the word out, the challenges in explaining and defending the ideas of life extension, and our roles in moving the field forward.
I stressed the fact that although we at Lifespan.io are passionate about the field’s success, we are also proud to be following strict journalistic standards by providing thorough and impartial coverage. In the end, this responsible approach fosters trust, which is indispensable for bringing more people behind the idea of life extension.
While scientists are obviously better at science, we in the communication and advocacy space might be better at explaining science as well as the philosophical and ethical aspects of life extension. Over the years, we have developed effective communication tools and approaches that our friends in the scientific community can tap into.
I felt genuine interest in our work coming from the audience, and the feedback that me and other participants had received clearly showed that organizing this panel was a great idea and that we need more such interactions in the longevity field.
The organizer’s take
Christin Glorioso gave her opinion on the talk:
Longevity biotech is an emerging phenomenon, and the progress is amazing. Many companies presenting were relatively early stage with very cool angles. In my opinion, BioAge’s successful Phase 1b trial was the most impressive result. I am also a fan of Juvena, which just had a successful Series A raise to go. The conference had a good variety of talks from senescence to aging clocks, including non-traditional animal models such as the ground squirrel and dogs. We learned from the funding-related talks that longevity is still a very underfunded area despite the recent acceleration in investment. Media work is required to raise public awareness, but we should be careful to avoid any pitfalls with pay to play and misinformation. Lastly, longevity is not just a vanity mission for the ultra-wealthy. Talks by Dr. Stacie Walton, Yvonne Dotson, and Jennifer Garrison highlighted that longevity is also a matter of equality for both BIPOC (with systemic racism contributing to shorter lifespans) and women (with reproductive equality).
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