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Zuzalu Talks Longevity: Highlights from the Conference

Real science took center stage at this conference.

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Keith at ZuzaluKeith at Zuzalu

Lifespan.io president Keith Comito presenting in Zuzalu. Photo: Arkadi Mazin

While the format of this conference was rather conventional, the venue was anything but. It was held in Zuzalu, which can’t be found on any map. Zuzalu is a unique “pop-up city” conceived by the tech entrepreneur Vitalik Buterin, creator of Ethereum, and a group of like-minded individuals to facilitate co-living and collaboration in fields like crypto, AI, and longevity. Zuzalu, located on the Adriatic coast of Montenegro, began its short history on March 25 and will be winding down on May 25.

VitaDAO, a decentralized science venture that we have extensively covered and collaborated with, was instrumental in organizing the longevity part of Zuzalu, including this 2.5-day conference featuring several big names in the field. Probably due to the audience being unusually diverse, many talks presented an overview of the current state of science in a certain subfield instead of focusing on new discoveries. As usual, Lifespan.io brings you the highlights, excluding the talks we were unable to attend.

Nathan Cheng and Stephanie Dainow on LongBio

The first talk of the conference was conducted jointly by Nathan Cheng, executive director of Longevity Biotech Fellowship, and Lifespan.io executive director Stephanie Dainow. It offered a short overview of longevity biotech, or LongBio.

The first slide informed the audience that longevity biotech is “the development of therapies that can treat or prevent multiple age-related diseases at the same time and increase healthy lifespan by targeting cellular or molecular mechanisms of aging”. However, it was immediately followed by a list of caveats, the first of which was that there is “no consensus on the definition”, which is probably expected of such a young field.

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Longevity-related biotechnologies are a motley bunch, and not all of them get funded equally. According to the presentation, the one that currently receives the most funding is cellular reprogramming, but that is heavily skewed by a few targeted investments, such as the 3 billion dollars poured in 2022 into Altos Labs. Regenerative medicine takes second place, while other technologies lag behind. Unfortunately, some very important approaches, such as extracellular matrix repair, receive very little funding or attention.

Longevity biotech, which was almost nonexistent just a few years ago, now has about 40 therapies in clinical trials and is expected to grow substantially in the following years; after all, aging is going nowhere. However, it is still only a small fraction of general biotech, with around 160 startups, less than 50 billion dollars in total evaluation, 13 billion dollars in funding, and just about 20 longevity-focused VCs.

Aubrey de Grey on damage repair and frontiers

Aubrey de Grey, founder, president, and CSO of Longevity Escape Velocity (LEV) Foundation, provided a review of the current therapies aimed at age-related damage repair. He noted that the seven “Deadly Things”, the age-related damages that he proposed more than 20 years ago, are still here, but the repertoire of possible fixes has grown considerably for every type of damage. This includes partial reprogramming as a potential cure for cell loss, senolytics for death-resistant cells, and so on.

De Grey also spoke about one of the largest and boldest animal trials in the longevity space, which is currently being conducted by LEV Foundation. The vast study tests four interventions and their various combinations in about 1000 mice (read all about it in our interview with de Grey). The interventions include rapamycin, a senolytic (specially formulated navitoclax), telomerase reverse transcriptase (TERT), and hematopoietic stem cell therapy (HSCT). The study’s clever design should enable scientists both to test combinations, a concept that was featured in many talks at the conference, and isolate the effect of each intervention.

Amy Proal on the human virome

Amy Proal of the PolyBio Research Foundation touched upon the often-overlooked topic of the human virome: the immense community of viruses that inhabit our body. Proal’s talk technically was not part of the conference, but we thought it was worth including here.

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Proal is known for her work on chronic inflammatory conditions, including long COVID. She noted that the immune system is shaped by the environment, including viruses. Most people have cytomegalovirus (CMV), which alters the immune system, including how it interacts with other viruses.

According to a recent paper cited by Proal, “dozens of viruses co-evolving with humans, including Influenza A virus, may actively distort human aging”. Viral activity is suspected to be one of the causes of age-related chronic inflammation (inflammaging). Viruses also affect mitochondrial metabolism and telomeres.

Another study has found that older people who had COVID-19 have a much higher risk of developing Alzheimer’s. In this context, Proal mentioned a recent spike of Alzheimer’s disease and dementia in India, a country brutally hit by the pandemic.

Viruses drive dysfunction by interfering with their hosts’ gene expression and epigenetic environment, dysregulating the immune response and hijacking their hosts’ metabolism for their own purposes. Many proteins made by viruses are similar in size and shape to human proteins and bind to the same receptors. When the immune system targets those pathogens, human proteins become collateral damage, which drives chronic disease processes.

Retro Bio has received a lot of attention

Retro Bio is a longevity biotech startup that has recently attracted a lot of attention (and maybe a bit of envy) after Sam Altman, founder of OpenAI, invested 180 million dollars in the company. Retro’s co-founder and CEO Joe Betts-LaCroix gave an update on the company’s situation and plans. On its website, Retro highlights its goal of adding ten years to healthy human lifespan. Betts-LaCroix added that Retro aims at becoming “the Pfizer of aging”.

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Indeed, despite its currently modest size, Retro is working in three directions simultaneously. One of its programs is centered around autophagy, with the target and the lead molecule identified, and human trials posed to begin later this year. Another one investigates manipulating blood plasma, with a clinical trial currently in progress. However, like many companies in the field, Retro has put most of its efforts into partial cellular reprogramming.

During the post-talk discussion, Aubrey de Grey’s tongue-in-cheek comment was that Retro had “only” 180 million dollars in their bank account, implying that it might not be enough to effectively pursue all three directions. However, Betts-LaCroix seemed confident in the company’s approach.

Yuri Deigin on the secrets of germline rejuvenation

Germline rejuvenation is what makes life on Earth possible. In a nutshell, organisms age, including their germline cells (the cells that will give rise to the organism’s progeny). However, for life to continue for billions of years, the new organism must be biologically new, so at some point, a rejuvenation event must occur. This event is still poorly understood, but many people think it holds a key to defeating aging. Yuri Deigin, CEO of YouthBio, gave a fascinating account of the current state of research into germline rejuvenation (reset).

According to Deigin, germline reset is what led him to work on partial cellular reprogramming, as the two phenomena are thought to have a lot in common. To rejuvenate themselves, germline cells have not only to reset their epigenetic landscape but also get rid of the intracellular damage associated with cellular age, such as misfolded proteins. One explanation involves damage dilution (dividing cells move cellular debris in such a way that one of the cells emerges from the division without damage). However, recent research shows that active damage clearance is taking place.

While germline reset is usually studied in multicellular organisms, Deigin discussed interesting experiments in yeast that showed sporulation resetting replicative lifespan, including by active damage clearance. Deigin also mentioned recent groundbreaking work in C. elegans worms by Cynthia Kenion, who is currently with Calico. Kenion showed that in those worms, most of whom self-fertilize, active clearance of damaged proteins from germline cells occurs.

Sergio Ruiz: update on Turn Bio

Turn Biotechnologies is one of the most interesting startups in cellular reprogramming. In his talk, Turn’s COO Sergio Ruiz called his company “a small startup trying to punch above our weight” while competing with behemoths such as the Altos Labs.

Like Deigin, Ruiz pointed out similarities between partial reprogramming and embryonic reset. He named cellular degradation as the root cause of chronic disease and gave an overview of his company’s attempts to counter it.

Despite its modest size, Turn is pursuing several directions. One of them includes rejuvenating T cells to make them more efficient in killing cancer. According to Ruiz, the company’s CAR T-cell program was created in a single year, highlighting the versatility of cellular reprogramming. While highly promising, CAR T-cell therapy is hampered by the fact that today, it is used as a second-line treatment after the immune system was exhausted by damaging first-line treatments. This is why rejuvenating exhausted T-cells can make a big difference.

Another Turn program involves rejuvenating skin. “We chose dermatology”, explained Ruiz, “because this way, we can talk do different industries. While trials are easier, you can still get the product out. With some caring about aesthetics, and others about wound healing, you have many shots on goal.”

According to Ruiz, rejuvenated skin, currently tested as xenotransplants in mice, exhibits youthful gene expression, including upregulation of collagen and elastin genes and downregulation of matrix metalloproteinases (MMPs).

Morten Scheibye-Knudsen on the quest for “the longevity molecule”

Prof. Morten Scheibye-Knudsen of the University of Copenhagen is trying to answer the question “What if therapeutics to slow down the aging process and prevent age-related disease already existed?” This project was one of the first to receive funding from VitaDAO.

Using machine learning, Scheibye-Knudsen’s lab is analyzing more than one billion prescriptions in order to understand how existing prescription drugs impact human lifespan. The lab has also applied text-based analysis to 33 million pathology reports.

This work has allowed Knudsen and his team to glean some interesting insights into aging, including its “chaotic nature” (“reports for older people are all over the place”, Knudsen said), which theoretically should complicate the task of countering aging. Knudsen also said that “males age faster but later, while females age earlier but slower”.

Metformin is a well-known example of a widely prescribed drug thought to have geroprotective qualities. However, analyzing life extension data on such drugs is hard because they are prescribed to people who are already unhealthy. According to Knudsen, their data shows that metformin, an anti-diabetes medication, increases 10-year survival in people older than 70 but is also associated with shortened maximum lifespan. This is consistent with multiple mouse studies that have found metformin’s positive effects on healthspan but not on lifespan.

Another result that Knudsen unveiled was that drug combinations seemed to potentiate the effect. Again, this is in line with current evidence. Drug combinations are becoming a hot topic in geroscience, despite being notably hard to study.

Danielle Ruiz (Everest Health Partners and Methuselah Foundation) on individualized longevity medicine

Many of today’s longevity conferences include at least one talk on longevity medicine, the budding field that tries to provide anti-aging care based on advanced diagnostics and our still-limited therapeutic options. Ruiz’ talk was unusual because it featured three individual case studies explaining how a longevity-oriented approach helped each patient.

One case study featured a woman in her 40s with a burden of disorders such as early menopause, non-alcoholic fatty liver disease (NAFLD), high inflammation, obesity, and prediabetes: a saddening picture found in many people around this age. The treatment included a combination of two prescription drugs (semaglutide and rapamycin), several supplements, healthy diet, and exercise. While this approach might seem trivial, recommendations of the same quality are hard to find in conventional medicine, which is focused on mitigating symptoms rather than addressing core causes.

The second patient was much older, burdened with hyperlipidemia, hypertension, prediabetes, arthritis, neuropathy, and emerging kidney failure. He came to see Ruiz fearing the onset of age-related frailty. The patient was prescribed a combination treatment of rapamycin and metformin as well as an apoB-lowering medication and several supplements.

Finally, the third patient, a relatively young, dedicated athlete, was experiencing a decline in his physical abilities. As it turned out, he already had hypertension, hyperlipidemia, insulin resistance, and impaired kidney function. This third patient was understandably wary of prescription medications, and his treatment regimen included only lifestyle changes and supplements. For more information on how people who are not yet old and are in good physical shape can unknowingly bring themselves to the brink of a metabolic disorder, we recommend the new book “Outlive” by Peter Attia, where he recounts a similar autobiographic story.

In all three cases, according to Ruiz, longevity medicine’s holistic approach showed its prowess, resulting in a sharp improvement in biomarkers and life quality.

Josef Christensen: a reality check on the stem cell industry

Josef Christensen, Chief Business Development Officer at Stem Medical, gave a sobering overview of the stem cell field. While it is poised to grow substantially in the following years, with dozens of stem cell therapies hitting the market or moving through advanced clinical trials, substantial manufacturing, administration, and regulation hurdles remain.

Manufacturing-wise, it is still hard to ensure product quality. The issue of cell loss during cryopreservation has not been fixed yet. Securing sufficient supplies is a problem as well, and it drives higher production costs. Switching from 2D (plates) to 3D (bioreactors) production constitutes a major hurdle that Stem Medical, according to Christensen, was able to clear.

Being able to store, thaw and administer stem cells might require more than a hundred steps for hospitals to complete. Procedures themselves can be so long and cumbersome that hospitals would not do them because they do not generate enough income.

According to Christensen, regulatory norms that apply to stem cell therapies “came out of small molecules and made their way to other modalities”. As a result, required stability margins might be impossibly high for stem cell therapies to meet. Regulation also discerns between homologous (based on the patient’s own cells) and non-homologous use, complicating things even further.

Jean Hebert on progressive brain tissue replacement

Jean Hebert of the Albert Einstein College of Medicine is one of the very few scientists working on what might be the hardest problems in geroscience: what do we do with the aging brain? Other organs can theoretically be replaced, providing a powerful rejuvenation boost, but not the brain, which contains the very self. Hebert’s answer to this conundrum is to replace brain tissue gradually, one small segment at a time, exploiting the amazing ability of the brain to adapt: neuroplasticity.

Hebert maintains that the damage to the extracellular matrix (ECM) is too diverse to be effectively targeted (“It would take addressing thousands of targets to make ECM young again”), which is why even repopulating the brain with new neurons (produced via cellular reprogramming) would not be enough. The answer, hence, is tissue-level replacement.

Hebert reported encouraging new results. Transplanting chunks of human brain tissue created from scratch into mice resulted in good engraftment and vascularization, with all iPSC-derived precursor cells surviving and differentiating in the graft. New chunks of brain tissue apparently integrated into the rest of the brain structure, producing reaction to light.

While it might be unsettling to imagine yourself undergoing regular brain tissue replacement, this might be an essential step in meaningfully increasing human lifespan. However, the indication Hebert is aiming at currently is not aging but stroke. Watch our 2021 interview with Jean Hebert.

Ohad Gafni on harvesting stem cells from “stembroids”

Gafni’s company Renewal Bio, based in Israel, only recently emerged from stealth mode, generating a lot of excitement. This company had developed a method of growing embryo-like structures in vitro in order to harvest various types of stem cells.

Gafni admitted that these structures, which he called “stembroids”, are still flawed compared to real embryos, but they are good enough to provide a source for those stem cells. Their similarity to natural embryos measured by single-cell RNA sequencing is more than 95%.

Renewal Bio has succeeded in growing its stembroids until approximately day 8, which is enough to harvest some but not all types of stem cells. The next milestone is reaching 28 days to be able to harvest hematopoietic stem cells (HSCs).

The company’s aim is to become the leading source of human stem cells for transplantation and research (tackling cell and tissue shortage). However, Gafni admitted that some regulatory hurdles related to stem cell research might still be in place. Interestingly, Israeli law is far more permitting when it comes to embryo-derived stem cells compared to US law.

Keith Comito on propagating philanthropy with dynamic NFTs

Lifespan.io president Keith Comito gave a talk on the intersection of longevity and emerging technologies such as NFTs. While many people consider NFTs to be a fluke at best, the technology actually provides for many interesting uses.

Comito focused on using NFTs to introduce elements of gameplay into philanthropic action. Unlike regular NFTs, dynamic NFTs can be changed after acquisition. For instance, one dynamic NFT sold prior to America’s 2020 presidential election was set up to change according to the election’s outcome.

This technology could be used to create Proof of Philanthropy (POP) NFTs. For instance, an image can contain a badge that changes its color to golden when the owner donates to charity or takes some other philanthropic action. This, Comito said, can “allow philanthropists to create new philanthropists”.

Being a much more diverse technology than most people think, NFTs can also be “soulbound”, i.e., non-tradable and bound to a specific individual, and demi-souldbound. Skillfully using such NFT “flavors” can nudge more people towards donating or otherwise contributing to the longevity field. Moreover, dynamic NFTs can be used to entice their owners to care for their own health.

Comito then touched upon decentralized clinical trials. Lifespan.io has crowdfunded several important trials, with one of the current projects being “Treating Alzheimer’s with Light and Sound.” Comito also praised Zuzalu as “a natural progression of the citizen science spirit”.

Björn Schumacher: sadly, we all have a DREAM

Prof. Björn Schumacher of Cologne University gave an update on one of the most important recent discoveries which was made in his laboratory. The researchers have discovered a previously unknown role for the protein complex named DREAM. Apparently, DREAM restricts DNA damage repair (DDR) in non-dividing somatic cells.

When the researchers introduced loss-of-function mutations into DREAM-producing genes, such mutants were much more capable of DNA damage repair than their wild-type counterparts and, consequently, resistant to DNA damage-driven aging. Essentially, mutated somatic cells behaved, in this regard, like germline cells where DREAM was not assembled, exhibiting much more efficient DNA repair.

When asked by Lifespan.io, what could be the evolutionary origins of this mechanism, Schumacher replied that the trade-off seemed to be increased fecundity in C. elegans that are able to assemble the DREAM complex. This looks like a clear example of antagonistic pleiotropy: a trait that is beneficial during the reproductive period but deleterious later in life. As such, it gets selected by evolution despite the unpleasant fact that it accelerates aging.

According to Schumacher, the DREAM complex can also be pharmacologically inhibited in mice and in human cells, which can lead to development of new anti-aging treatments.

Peter Fedichev’s theory of aging

Peter Fedichev, co-founder of Gero, has made waves with his theory that might upend our notion of aging. Fedichev, a physicist by training, claims that there are essentially two types of aging: one of them applies more to short-lived species such as mice, and the other applies more to long-lived species such as humans or naked mole rats (NMRs).

Mice, which live for no more than 2-3 years, exhibit much less stability; basically, things start going south very quickly in what looks like a chain reaction. This also means that anti-aging treatments that help restore stability have a relatively high impact, which is what we observe with drugs such as rapamycin.

Humans, on the other hand, remain in a relatively stable “NMR-like” state for decades, with our powerful repair mechanisms maintaining homeostasis. Here, age-related damage accumulates slowly, but, according to Fedichev, there is a dark side to this stability: the effect sizes of anti-aging treatments are low, and true rejuvenation is extremely hard to achieve.

However, in accordance with the Gompertz curve, as humans near life’s end, they start aging more like mice than like NMRs. Returning to homeostasis becomes harder. At this point, which is associated with the onset of age-related frailty, anti-aging treatments might actually show better results. Frailty and aging, according to Fedichev, are “different phenotypes in humans”, and treatments that tackle the former probably don’t work on the latter and vice versa.

This theory offers good news and bad news. On one hand, aging can be stopped at virtually any point, on the other hand, it can hardly be reversed (“true rejuvenation”). While Fedichev’s theory has received a lot of attention, it is not considered proven. Recently, Gero entered a collaboration with Pfizer, gaining access to millions of medical records that might shed more light on the subject. Stay tuned for our upcoming interview with Peter.

Brian Kennedy on targeting aging directly

Brian Kennedy is working at the National University of Singapore on small molecules with anti-aging properties. Kennedy began his talk by admitting the importance of anti-aging research for Singapore, where by 2040, there will be one non-working person for every two working.

Kennedy’s lab is working on numerous compounds, including metformin, alpha-ketoglutarate (AKG), glycine, urolithin, and gemfibrozil. One of the most important aspects of this work is finding the targets. For instance, Kennedy said, we still don’t know what the target of metformin is, despite this drug being widely used for decades. The lab discovers targets using heat, because a protein is less likely to denaturate if it is bound to the drug (i.e., if it is this drug’s target).

Gemfibrozil, an anti-cholesterol drug rarely mentioned in the longevity context, is of particular interest to Kennedy, who is starting a company to develop gemfibrozil-based therapies. This drug, which probably reduces amino acid uptake, has shown a large effect on frailty in mice.

Importantly, according to Kennedy, multiple supplements in mice sometimes counteract each other’s effect. For example, berberine and AKG cancel each other out. This should come as a warning for people who take numerous anti-aging supplements without accounting for possible interactions that are mostly still unknown to science. On the other hand, some cumulative effects have already been proven, such as the synergy between rapamycin and acarbose.

Closing panel: what about fundamental science?

During the closing panel, Peter Fedichev, Aubrey de Grey, Björn Schumacher, and Brian Kennedy discussed the problems and opportunities that geroscience is currently facing.

Kennedy lamented the difficulty of getting funding “to dig into basic science questions, such as what is aging”. This might be the darker side of the growing interest in geroscience, since even the NIH is currently mostly interested in “translation, translation, translation”, he said.

Other participants sided with Kennedy. Schumacher mentioned the groundbreaking discovery of sporulation reset in yeast, adding that “nobody works in yeast”, because it is considered too basic and irrelevant to translation. “We need to answer more fundamental questions in order to fix healthspan,” he said.

Aubrey de Grey agreed that the pendulum is currently “going the other way”, towards translation at the expense of fundamental science, the main focus being on the easy part of translation: quickly getting impressive results that are not necessarily translatable. “We must in parallel be working on more impactful, difficult interventions”, he said. “It’s not a zero-sum game, those two can help each other.”

As the discussion was drawing to a close, Peter Fedichev suggested, being “contrarian to himself”, that chasing maximum lifespan extension should not be the main goal, since a person has only a one-in-a-billion chance of achieving this maximum lifespan, which currently stands at about 120 years. This makes improving healthspan (and hence the probability of achieving this maximum lifespan) a much more pressing issue.

Zuzalu photo

From left: Peter Fedichev, Aubrey de Grey, Björn Schumacher, and Brian Kennedy. Photo: Arkadi Mazin

Stay tuned for our upcoming full coverage of Zuzalu.
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About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.