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Building a Future Free of Age-Related Disease

Public Longevity Group

Lifespan Research Institute Launches Public Longevity Group

[Mountain View, September 17, 2025]Lifespan Research Institute (LRI) today announced the launch of the Public Longevity Group (PLG), a new initiative focused on bridging the cultural gap between scientific breakthroughs in aging and their public acceptance. To kickstart its work, PLG has opened a crowdfunding campaign to develop tools that measure and strengthen public trust in longevity science.

While the science of longevity biotechnology continues to advance, skepticism and cultural resistance limit progress, with some studies showing that more than half of Americans would reject a safe, proven therapy to extend life. This hesitation poses risks of raising costs, delaying health-promoting regulation, and slowing the delivery of treatments that could combat age-related diseases and extend healthy lifespan.

“The breakthrough that unlocks all other breakthroughs is public trust,” said Sho Joseph Ozaki Tan, Founder of PLG. “Without it, even the most promising therapies may never reach the people they’re meant to help. PLG exists to change that.”

“Persuasion is a science too,” said Keith Comito, CEO of Lifespan Research Institute. “To bring health-extending technologies to the public as quickly as possible, we must approach advocacy with the same rigor as our research. With PLG, we’ll be able to systematically measure and increase social receptivity, making the public’s appetite for credible longevity therapies unmistakable to policymakers, investors, and the public itself.”

PLG is developing the first data-driven cultural intelligence system for longevity—a platform designed to track real-time sentiment, test narratives, and identify which messages resonate and which backfire. Early tools include:

  • The Longevity Cultural Clock: a cultural barometer mapping readiness and resistance across demographics and regions.
  • Sentiment Dashboards: real-time monitoring of public, investor, and policymaker perceptions.
  • Narrative Testing Tools: data-driven analysis that will enable robust pathways to public support.

The crowdfunding campaign will provide the initial $100,000 needed to launch these tools, creating the cultural foundation required for healthier, longer lives.

With a lean, data-driven team, the group aims to provide open-access cultural insights for advocates and policymakers while offering advanced analytics to mission-aligned partners.

Campaign Timeline:

  • Campaign completion: November 2, 2025
  • Dashboard development: Dec 2025 – Feb 2026
  • First survey deployment: Feb – Apr 2026
  • Beta dashboard launch: May 2026
  • First public insight report: June 2026

Supporters can contribute directly at: https://lifespan.io/campaigns/public-longevity-group/

The PLG campaign is sponsored by the members of LRI’s Lifespan Alliance, a consortium of mission-aligned organizations that believe in the promise of extending healthy human lifespan. Newly-joined members include OpenCures, AgelessRx, and Lento Bio.

About Lifespan Research Institute

Lifespan Research Institute accelerates the science and systems needed for longer, healthier lives by uniting researchers, investors, and the public to drive lasting impact. LRI advances breakthrough science, builds high-impact ecosystems, and connects the global longevity community.

Media Contact:

Christie Sacco

Marketing Director

Lifespan Research Institute

christie.sacco@lifespan.io

(650) 336-1780

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Forever Healthy Foundation

Forever Healthy Foundation Launches Evipedia.ai

The Forever Healthy Foundation today publicly launched evipedia.ai, an open online encyclopedia of in-depth evidence reviews covering more than 500 health and longevity interventions, including first-generation rejuvenation therapies, supplements, botanicals, lifestyle protocols, and more.

Evipedia was built to solve a problem familiar to anyone navigating the longevity field: the literature is vast, fragmented, fast-moving, and full of marketing posing as evidence. The encyclopedia distills the current state of evidence for each intervention into a structured, transparent, and continuously refreshed format — free for anyone to read.

“Evipedia is the tool we always wished we had when we started our journey in personal longevity. Our goal is to empower individuals with the knowledge to make informed decisions about their health and longevity.”

— Michael Greve, Founder, Forever Healthy Foundation

What’s in Evipedia

  • 500+ evidence reviews across categories including whole-body therapies (HBOT, PEMF, cryotherapy), brain health, skin rejuvenation, hormone optimization, medications, blood and plasma therapies, complementary cancer approaches, foundational habits, diets, foods, probiotics, botanicals, isolates, and more.
  • A dual structure for every entry Each intervention has a one-page Quick Reference Sheet for at-a-glance protocol, benefits, risks, contraindications, and monitoring, plus a Full Evidence Review for in-depth analysis.
  • Continuous updates Entries are refreshed every 4-6 weeks to reflect new research, keeping reviews current rather than freezing them in time.
  • Stable, shareable permalinks Every intervention has a fixed, short URL and a purpose-designed social sharing card — ideal for citing a compound in a supplement stack or anchoring a claim in an online discussion.

Built on AI4L — open-source, audit-based prompting

What sets Evipedia apart from other AI-assisted health content is the methodology behind it. Every review on Evipedia is produced using AI4L, Forever Healthy’s open-source framework for generating high-quality, well-structured, and hallucination-free evidence reviews, available on GitHub for anyone to use.

At AI4L’s core is a novel “Audit-Based Prompting” approach: each draft is iteratively audited against an extensive structured checklist and revised until it passes — making outputs more accurate, less prone to hallucination, and far more consistent than single-shot AI generation.

Full audit and quality transparency

Every “Quick Reference Sheet” and “Evidence Review” on Evipedia is accompanied by its audit report, which outlines the detailed audit criteria and the history of audits and fixes applied to the documents.

About the Forever Healthy Foundation

The Forever Healthy Foundation gGmbH is a German nonprofit with a single mission: to enable people to extend their healthy lifespan and benefit from the rapidly approaching breakthroughs in human rejuvenation. More at forever-healthy.org.

Resources

Press contact

hello@forever-heathy.org

Todd White Interview

The Thalion Initiative: A New Non-Profit With Big Ambitions

The longevity field remains small and starved for resources, especially the subfield devoted to the fundamental biology of aging, despite near-universal agreement that solving aging requires understanding it first. With VCs looking for clinical successes and state funding drying up for many projects, some enthusiasts are turning to a nonprofit model.

That path is anything but easy, particularly when you’re trying to secure donations in the hundreds of millions. Which is exactly what makes the Thalion Initiative so special: in the works for a good couple of years, it has now surfaced with strikingly ambitious plans.

Thalion has several top-tier names in geroscience as advisors, including Brian Kennedy, Vera Gorbunova, Vadim Gladyshev, Emma Teeling, Michael Levin, João Pedro de Magalhães, Steven Austad, Peter Fedichev, and many others. Max Unfried and Maria Marinova serve as Scientific Directors, while Todd White has taken on the role of Managing Director.

Thalion will fund research across five key areas: embryonic rejuvenation, comparative biology, synthetic biology, tooling, and modeling. This is far more than an eclectic collection of unrelated projects – it all feeds into a single plan spanning more than a decade. Intrigued and excited, I sat down with Todd White to discuss Thalion and its role in the longevity landscape, and this role promises to be considerable.

I know you from VitaDAO, but yours is one of the most unusual journeys into the longevity field. Let’s start there: describe how you got into this, and especially the last leg, from VitaDAO to Thallion.

It is unusual because I spent the first 25 years of my career in telecommunications. I’m an electrical engineer by training, not a biologist – which is interesting, because once I got involved in longevity, I noticed how many people in the field aren’t biologists either.

In 2018, a close family friend died suddenly from an autoimmune disorder. He was 52; I was 48. Processing that loss pulled me into reading about autoimmune disease and, more broadly, mortality.

In 2019, because of the telecom world, I was often around high-net-worth individuals, and longevity came up. Two themes emerged. First, most of them didn’t believe longevity scientists understood the science well enough to make real progress. Second, nobody had ever come to them with a fully fleshed-out plan for how you’d actually tackle aging. So, I foolishly put my hand up and said, “Let me get this straight – if someone came to you with a real plan, you’d be interested in pursuing it?” And the answer was generally yes.

That was November 2019. Then COVID shut everything down. Around 2021, VitaDAO came onto the scene, and like everyone else I was at home listening to Nathan Cheng talk about longevity – so I blame him. Between that and Aubrey de Grey’s book, those were the two things that got me going, and VitaDAO seemed like an interesting way to learn more about the space.

But, by the end of 2023, I’d realized that funding individual PIs in individual labs, which is what we were doing at VitaDAO, wasn’t going to move the needle. The science felt too small. In fairness to those PIs, they’re given a certain amount of money – rarely enough to do what they’d really like – so they run the experiments they can and hope for the next grant. Crypto, for all its easier access to capital, fell into the same small-pot, individual-project pattern.

The push toward translation worried me, too: if you’re not getting government grants, you go to private equity, and private equity needs a return. VCs back small biotechs hoping for a commercializable drug, but in many cases, a whole layer of fundamental research was still missing. Getting to a real therapeutic target takes far more money than most people in longevity ever see — it’s almost a lottery ticket.

So, I sat down with two colleagues I’d met through VitaDAO – Max Unfried and Maria Marinova – and said we needed to do something different. We set out to figure out what a real, solid plan would look like and flew ~30 aging researchers – all the usual suspects, Vera Gorbunova, Vadim Gladyshev, David Gems, that whole group – into Birmingham, England for a week. We told them, “We’re not here to talk about funding what you do in your labs. Our goal is to talk about what it will take to move the entire field forward.” We argued it out for a week, then met every week for the next nine months, including another week of in-person workshops in Boston.

I’d have loved to be a fly on the wall.

It was fascinating. Once you got past “this is what I do in my lab and what I need for my next paper and grant,” everyone became very open – a very different experience than a conference. We came away with about 170 questions that, if answered, would completely open up the field. João Pedro de Magalhães, from Birmingham, led turning that into a paper, published in GeroScience in November 2025 – the top 100 open questions.

From the full list, we then asked what research we’d need to do, and in what order, to answer them. That gave us 16 projects for Thallion across five pillars: comparative biology, embryogenesis and germline rejuvenation, synthetic biology, tooling, and computational biology. We built it into a 220-page plan and then had to get it resourced – that was most of 2025, and it’s still ongoing. What made the year so dynamic was that the US government cut so much funding – NIH, NIA, NSF all cut back – which changed the dynamics for a lot of people.

Not a great time to be raising money.

Some of the worst. But in one sense it was good, because it focused the people who would fund this kind of research on what really matters to them. One thing became clear: longevity has a terrible reputation right now. So, we decided we wouldn’t disclose who’s funding us unless they want to be public – the concern was almost entirely reputational.

People have worked on longevity for 25 years, and the serious research takes a long time, but in that window a lot of people came in selling supplements and things that don’t make a difference, and it poisons the well. We’ve ended up spending more time defending the field than anything else. Nobody really questioned the science we wanted to do; they questioned how funding it would affect their personal reputation.

Which is unbelievably unfair.

It’s tremendously unfair, and I’m frustrated for the PIs – top researchers being painted with the same brush as someone overclaiming results. But I’m glad I went through it, because now I understand better than ever how hard it is for a researcher to get the resources they need. And private equity is part of the problem too, because they want a quick return, and this work is not quick.

I want to circle back to public relations later, but first I want to understand what Thalion is. Your work is mostly about fundamental aging biology and laying the groundwork, including the tools, because retooling the biology matters enormously. What problem are you trying to solve, and what’s the roadmap?

A lot of biologists do a lot of guessing, because they don’t have the data to prove that what they think is true actually is – aging is longitudinal and the system is very complex. Thalion has three phases over a 15-year scope: the first runs from now to around 2033, the second from roughly 2033 to 2038, and so on. This first phase is mostly building tools and datasets – filling the gaps we need to do good science. We won’t really get to the science until around 2029 or 2030. You’re seeing the same logic on tooling at organizations like the Arc Institute and CZI, with their virtual-cell work and AI modeling.

Take comparative biology. Everyone talks about longevity, but we have very little proof that dramatically extending lifespan is possible – except in evolutionary biology. We have bowhead whales, naked mole rats: living, breathing examples of lifespan variation.

Sometimes across really close species, which means longevity can evolve relatively quickly, without fundamental changes to the organism.

Exactly. So, the first big project – actually, the biggest of them – is a mammalian biobank: 200 species with extremely deep -omics. Most biobanks collect tissues and do a genome sequence; we’re doing genomics, methylomics, transcriptomics, proteomics, metabololipidomics, single-cell or spatial – all the building blocks of life, very deeply. The 200 species run from the shortest-lived to the longest-lived, with a progression through the middle — the full range of lifespan variation in mammals.

Everyone talks about how AI will change everything, but I think people are over-indexing on it – not because it isn’t an incredible tool, but because we can’t yet teach it what to look for. That’s a lack of data, and not just more data: it has to be deep data. The biobank won’t just be tissues; it’ll be the multilayered -omics that give detailed, species-by-species information. That project alone is between $100 and $120 million, which would make it the biggest and most information-dense mammalian biobank of its kind ever built with over 2.5 million datapoints.

On tooling: part of the reason we have to guess is that we can’t see what’s going on. As soon as you can see a problem, you can start working out how to solve it. There are two main areas: microscopy and mass spec. One project is to improve the standardization and information extraction from mass spec; the other is to vastly improve microscopy.

The key is to do it in a living cell, as I understand.

That’s right – label-free, living tissue. We need those tools for our -omics. People ask why we don’t just use the biobanks that are already out there, but we need to collect tissues in a way that lets us analyze them with today’s tools and then, in five years, reanalyze with our own far-higher-resolution tools. That’s also why the biobank has an iPSC component.

That’s one of the most interesting parts – it starts from 50 species, I think.

Initially 50. We have some flexibility in the budget and may do iPSCs for all 200 species, but the commitment to our patrons is 50 to start.

Then comes computational biology. The biobank itself is huge — we’re scoped for 60 petabytes of storage, with a lot of GPUs, roughly the same scale as what CZI announced they were providing access to for researchers.

As we built the platform, we went back to first principles. You’ve been around the field a while: first it was longevity, then radical life extension, then healthspan. Those are all aspirational, marketing-style labels. We decided we’d say we do aging biology. So, the first question became: what is aging? Vadim Gladyshev published a paper in 2024 showing that biologists don’t even agree on what aging is. We tackled that head-on, ran a year of computational experiments, and came away thinking that aging isn’t actually the real problem.

I would argue that aging is a proxy for the problem. The real problem is something called homeodynamic remediation – an idea that goes back to the work of Robin Holliday and Suresh Rattan 20 years ago. Think about Parkinson’s: we call it an age-related disease because it usually shows up later in life, but any good description of the problem has to handle the edge cases. Michael J. Fox developed early-onset Parkinson’s at 29, near the peak of his resilience. Aging didn’t give him Parkinson’s – so why did he get it? It comes back to homeodynamics, the body’s ability, or inability, to repair damage.

In other words, maintaining homeostasis.

Exactly. Homeostasis is maintaining stability, and the systems that maintain it – clearing senescent cells, DNA repair – are what contribute to homeodynamics. I always channel my inner Peter Fedichev here, because Peter is a theoretical physicist who loves math, and we built a mathematical model to capture this. Internally we call it our homeodynamic remediation framework, or HDR, and all of our computational work currently goes through that lens. So, we’re challenging the assumptions in biology as we go – the quality of the data in biobanks, and even what the right question is.

Tell me about the embryonic reset part, where you have Vadim Gladyshev and Michael Levin working together. That should get every longevity enthusiast fired up. You want to combine embryogenesis with bioelectricity, which I find especially interesting.

Everything in biology is so siloed – senescent cells over here, bioelectrics over there. This comes back to HDR: rather than reduce the science, we want to embrace the complexity, and when you do, you realize bioelectric patterns apply to a lot.

We’ve been able to show where Michael Levin’s work makes sense and how it weaves in. Embryogenesis is the clearest example: at conception, egg and sperm come together, and over the next few days, as you move through the zygote and the development cycle, all the damage from both parents disappears. You get a cellular-level reset – ground zero – and then development moves forward. That reset is the key to how we rejuvenate cells, and it’s part of homeodynamic remediation: at that early stage, the system says, “There’s damage here; we have to fix all of it before we keep developing a baby.” There’s a bioelectric component to that first step, though I can’t say too much about it.

Why not?

Because that’s Michael’s research, and there’s IP involved. It’ll be disclosed as we go, but Vadim’s thinking and Michael’s thinking are coming together on how you get there. For now, we’ll be working mostly with mouse embryos and iPSCs, because of the moral issues around human eggs. So, one project is characterizing embryogenesis and the impact of bioelectrics in those early stages. Some of that work will also apply to the iPSCs – build the biobank, get the tissues, create iPSCs for different organs, then apply embryogenesis and bioelectric techniques across species. That will tell you a lot you couldn’t otherwise know.

Your work still comes down to funding particular projects and labs. The difference you’re proposing is to tie it all into one complete picture, a grand plan where the parts fit into each other. But can you tell me something about the funding? I’ve heard pretty insane rumors – including that you’ve raised 700 million.

That’s not crazy, in this sense: the total spend over the next eight years to do all of this research is $710 million, and we’ve been raising against that figure. Nobody has walked up with a single $710 million check. Different people have expressed interest to fund different projects – all milestone-driven, some general support. It’s a microcosm of everyone funding this research: some see value in the biobank specifically, some the embryogenesis or Michael Levin’s work, some the evolutionary side. A lot of my effort has been bringing people together and showing how, by helping solve one piece, they help unlock the others.

Now we have to deliver, and there’s a lot of skepticism — you want a lot of money, what guarantee is there that you can execute? Phase one is actually fairly straightforward: it’s data, with very little technical risk. There’s logistical risk but not technical risk, because we’re not stepping into the heavy-duty science yet. A biobank isn’t trivial, but most of it comes down to logistics — getting out there, collecting the right samples the right way, doing the omics work, which is the expensive part, and building the datasets.

You said you gave donors the choice to be named or not, but now you’re saying you can’t disclose any of them. Is that an organization-wide policy?

This is not really a policy – if tomorrow some billionaire decides to say, “I put this amount into Thalion,” that’s fine.

But nobody has said it yet – nobody wants to be openly associated with this?

Nobody yet.

That sounds frustrating, and it’s not ideal for your PR that the whole thing is so secretive. It would help to have a person, or a few people, who could serve as a public face.

The view was: when you have something concrete to release – the biobank, published work – there may be a reason to say something. Until then, no.

So even finding donors is…

Word of mouth. It’s all very quiet. The rationale comes back to reputation – and some of it is political: because of the way the current US administration has acted, a lot of those same potential patrons are very cautious about what they say publicly. Between the FDA and loss of US funding, there’s a sense that people are holding on and just trying to get through this administration.

That’s interesting, because from what I’ve heard, this administration is actually warming up to longevity – more than the previous one, in this particular respect.

True on one level. I’ve been involved in the Right to Try efforts in Montana and New Hampshire, opening up access to treatments. On the other hand, you have people saying they don’t want mRNA vaccines at the FDA – and mRNA and lipid delivery are a big part of how you deliver gene therapies and epigenetic reprogramming. You can use viral vectors, but mRNA is part of it.

So, there’s real uncertainty. Last year was firefighting, just dealing with life. This year, people are starting to come out of the woodwork – people who told me a year ago, “I’ve got to get through this administration stuff first,” are coming back, though still cautious. A lot of them have shifted money away from foundations into donor-advised funds, partly because they can give anonymously.

Going back to the programs – the comparative-biology program is vast and has all the right names. You’ve described the biobank, but other projects sound exciting too, like the chimeras, which seems the furthest off.

Most things build off the biobank. Once you have all that deep -omics data, you try to isolate the mechanisms that control lifespan, whatever they turn out to be. The obvious move is to take a short-lived mouse and genetically manipulate it to live longer.

So, it goes biobank, iPSCs, then transgenic mice. People do this with one or two genes, but once you want to manipulate four, five, six, eight at once, it becomes a real endeavor. You can breed mice to introduce genes over time, but to translate to humans, you obviously can’t tell people to have children and see if it works – you have to deliver the whole package as a gene therapy, so there’s real effort going into delivery.

Which is where the chimera project comes in – much more challenging technically, it lets you put cells from long-lived species into the embryos of short-lived ones. It’s such a long timeframe that it inevitably brings me back to the funding question: do you have any long-term commitments?

All commitments are targeting Phase 1 only. Part of the reason we structured it that way – beyond the fact that Phase 1 is already a lot of money – is that the plan will change, and we’ve been open about that. We’ll learn things that make us decide not to go further with a given project; we’re not going to fund it all the way through no matter what. The data of Phase 1 is fairly self-contained, so that’s what we’ve raised against. We have ideas and a good sense of the next two phases, but they may change.

There are a lot of moving parts, and you can’t start everything at once or move at the same pace on all of them.

Mostly, yes. In comparative biology, you can’t get into the chimeras and transgenic mice until you know which genes you’re working with. So, the biobank, the collection, and the -omics are really the next five years; the chimeras and transgenics come later.

As you said from the start, your work is heavily affected by public attitudes toward longevity. Do you have any plan to address that specifically?

No. We made two decisions early on. First, we’re not getting into clinical trials in this phase. There was a push from the researchers to go do things in humans, and we said we’re not ready at all. I hope I’m wrong – I hope BioAge comes out with drugs and some of the well-funded companies succeed – but we’re not doing the clinical side at this point.

Second, we’re not getting into the narrative. Part of the problem is that everyone keeps trying out narratives to see which one works, and it’s never been consistent. People like Nir Barzilai have moved to “geroscience” as the label, because they ran into the same “this is all snake oil” perception.

Other than some policy work with the A4LI – the Alliance for Longevity Initiatives – we’re staying out of communications. It would be great if the public could convince the government to put billions into this the way it does for Alzheimer’s, but we don’t see that as our job; it would need far more money, and there are already enough people interested. The real shift will come when a company like BioAge or Life Biosciences actually puts out a drug that can be called an aging drug. If one of them gets a Phase 2 and Phase 3 result that genuinely works, that changes the dynamic overnight.

Hopefully.

From a credibility standpoint, that’s what will make the difference. As for communicating it more widely – to some people it matters, to others it doesn’t. Because it doesn’t feel imminent or urgent to most people, it doesn’t get the airplay, and I don’t think we’d add anything unique to that conversation.

Fair enough. It’s just that you started from how hard it’s been to reach donors because of the worsening public climate around longevity. There is only a handful of small organizations trying to defend the idea of life extension. I’d argue that longevity does get airtime and attention, but in very unflattering ways, like with Kara Swisher’s new CNN show. It genuinely worries me that the field hasn’t been able to put up much of a defense.

It’s definitely had an impact on raising money, but it really only comes up when I’m in a room being grilled for an hour. When I started raising funds, I answered that question right up front. I usually walk in and say, “The longevity field is a mess. There’s so much snake oil – and yet there’s a core of genuinely talented researchers doing real science who are being painted with that brush unfairly. I’m here to correct that.” And yes, this probably won’t work – one figure on our site is that only 1.2% of preclinical drug assets make it all the way through. You lose nine out of ten before you even get to the FDA, and nine out of ten after that.

If you’re an engineer, the argument is: in what other field could you walk in and say, “I’m going to succeed 1.2% of the time,” and not be shown the door? Nobody pays for a 1% success rate – yet we do exactly that, routinely, in medicine, and we consider it acceptable.

That’s exactly one of the things I find most infuriating – that people can’t extend the norms they accept in medicine to longevity.

It comes down to desperation. If you have a family member suffering from Alzheimer’s, you see it; it causes a visceral reaction, so even a desperate option gets support. Same with cancer. In those cases, the immediate, physical suffering gets the response; the squeaky wheel gets the grease. Aging doesn’t have that. Even “100,000 people are dying every day” isn’t urgent enough, because it doesn’t carry the emotional connection of watching your grandmother slowly waste away.

So, when I walk into a room with someone who can write a check, if they have an emotional connection to it, that’s usually why they took the meeting in the first place — they have staff to handle everything else. If I’m in the room at all, I feel I’ve already come a long way.

What usually moves people is that a family member or a friend died of an age-related disease, rather than the idea that they themselves are going to die?

Right. Elon Musk is a good example. His attitude is, “Yeah, aging sucks. It’s an engineering problem. I’d like to wake up and not hurt.” He’s not worried about dying; he’s worried about whether his back is going to slow him down before ten meetings. It’s the immediate short-termism.

It’s always interesting to hear from someone who’s actually been in the room with wealthy individuals and understands how they think about aging.

In many ways they’re not so different from people who aren’t wealthy, but they do think about it differently. They’re used to money buying solutions – when they have an engineering problem, they buy more talent and the engineers deliver. If Elon has a problem with a rocket motor, he gets everyone in a room and asks, “What are we doing about it? The metallurgy is wrong? Then we’ll get someone to make the metal.” It’s a very can-do attitude.

My ideal patron is someone from a tech background who has also lost money in biotech, because then they understand the challenges. They come to me and say, “You want my money – what are you going to do differently?” That becomes the conversation, and at least I’m not educating them. I’d much rather have someone who isn’t naive and will ask the hard questions, because otherwise, three years out, they’ll ask, “Why don’t I have a drug for aging yet?” I want someone who understands this is a long haul – but the sooner we start, the better chance of succeeding we have.

What is your general read on where the field sits in terms of science, biotech, regulation? We’ve talked a lot about public perception. Where do nonprofits and citizen science fit in the long term?

I’m encouraged. If you’re a small biotech, it’s probably the most encouraging part of the space, because impact investors tend to be more patient – but the amounts are small, enough to get you to a Series A or B.

The science is coming along. Realistically, longevity hasn’t gotten its due: if we’d had cancer-level funding for even five years, we’d be miles ahead, simply because you can cover more ground faster. Everyone’s doing great work with a relatively tiny amount of money.

But, we still have a long way to go, and it’s naive to think AI is just going to magically solve it. AI is a fantastic tool, but as far as I can see, we’re going to fail faster and cheaper – the end result won’t be that different. Maybe a drug candidate costs $2 million to reach a trial instead of $4 million, but its odds of success are still about one in ten. Efficacy is the thing I don’t see AI solving, because it’s trained on what we already know; it doesn’t synthesize drug candidates, it sifts data and proposes solutions, but no better from an efficacy perspective than a good PI could.

I’d actually argue AI will help more on your side – fundamental biology, understanding aging – if you feed it a lot of data, which is exactly what you’ll be generating. That’s where it can shine, more than in picking drug candidates.

Right, and that takes time. For the next couple of years, there’ll be a lot of noise about how great AI is going to be, but the real value, at least from our perspective, comes in three or four years, once we have the datasets. You see this everywhere now – ARIA and others talking about building datasets for AI – because they’ve realized they don’t have the resolution or the data density they need to make good decisions.

Should we expect milestone updates from Thalion?

Yes. For the biobank, if you go to biobank.thalion.global, that’s essentially the scorecard – you’ll be able to watch our progress, and we’ll do the same for the other projects as they develop. It’s all part of letting people measure our impact.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Rejuvenation Roundup May 2026

Rejuvenation Roundup May 2026

Approaches that modify the processes of aging at their roots have gone well beyond basic research and into therapies intended for the clinic within the next few years. Here’s how the field has advanced in May.

Team and activities

LIN ReportThe Longevity Investor Network Looks Back at 2025: Through curated monthly pitch sessions, educational seminars, collaborative diligence, and ecosystem-building events, LIN provides a structured platform for investors to discover, evaluate, and support companies working at the forefront of aging biology and rejuvenation biotechnology.

Interviews

Junyue Cao on How the Body Ages, Cell by Cell: Dr. Junyue Cao is a professor at the Rockefeller University, and his lab develops ultra-high-throughput single-cell technologies and applies them to the biology of aging.

Matthew O'ConnorMatthew O’Connor on Cyclarity’s Successful Phase 1 Trial: Most cardiovascular trials focus on lowering LDL cholesterol or reducing inflammation to slow disease progression. UDP-003 targets the root cause: toxic 7-ketocholesterol (7KC) inside macrophages and soft plaques.

Developing a Drug To Reverse Heart Disease: We have spoken with Reason from Repair Biotechnologies about his company’s lead candidate, REP-0004, a drug targeting the liver to reduce excess intracellular free cholesterol.

Advocacy and Analysis

Radical Life Extension: This book explains aging as accumulated biological damage, examines why most longevity ideas fail, and outlines three strategies—biostasis, replacement, and bioengineering—that could allow humans to live dramatically longer lives.

Clinical trialCurrent Clinical Trials of Alzheimer’s Drugs: A group of researchers published an annual report on the clinical trials that are testing drugs for Alzheimer’s disease. Overall, they reported an increase in the number of trials, with 158 drugs investigated across 192 trials.

Harvard Publishes a Longevity Report for the General Public: The report, titled “Pathways to Longevity”, introduces several important longevity concepts to the general reader and is another sign that the field is coming of age and entering the mainstream.

Research Roundup

Robot doctor“Thinking” AI Outperforms Human Doctors on Real-Life Data: A new study has pit an advanced large language model against human physicians in tasks involving complex reasoning, treatment recommendations, and messy real-world patient records.

Creatine Shows Synergy With Exercise in Older Adults: In a new study, the popular supplement creatine seemed to add to some of the beneficial effects of power training.

Gut bacteriaHow Intestinal Aging Encourages Harmful Bacteria: In Aging Cell, researchers have elucidated the relationship between intestinal aging and age-related changes to the gut microbiome.

GLP-1 Drugs’ Muscle Effects Similar to Ordinary Weight Loss: A new study suggests that GLP-1 receptor agonists do not affect muscle mass any more than weight loss caused by caloric restriction, and this appears to be true for strength as well.

T cells attacking cancerNew mRNA Therapy Destroys Cancer by Improving T Cell Priming: Scientists have found a way to drastically ramp up mouse immune responses to cancer along with flu and COVID-19.

CRISPR-Based System Targets RNA and Kills Cells on Demand: Scientists have devised a CRISPR-based tool that can kill cells carrying a specific strand of RNA. The tested targets include cancerous and virus-infected cells.

Identifying DNAUntangling Cellular Senescence at Its Roots: In Aging Cell, researchers have described the differences between primary and secondary senescent cells, comparing radiation-induced senescence to senescence induced by the SASP.

How an Oxidative Stress Regulator Makes Cataracts Worse: Researchers have outlined a key receptor and protein involved in the formation of cataracts, paving the way for potential treatments targeting them.

Mitochondrial membraneMitochondrial Aging Linked to Losing Crucial Membrane Lipid: Scientists have found that the levels of phosphatidylcholine, the most abundant lipid in mitochondrial membranes, decline with age, driving mitochondrial aging in worms and possibly humans.

How Omega-3 Fatty Acids May Alleviate Kidney Disease: Researchers have discovered the role of cellular senescence in the interaction between omega-3 polyunsaturated fatty acids (PUFAs) and chronic kidney disease (CKD).

BrainTau Protein Is Crucial for Encoding Long-Term Memory: Scientists have uncovered an unexpected function of the tau protein, which is mostly known for its role in Alzheimer’s and related disorders: helping encode long-term memory..

Cardiovascular Health During the Menopausal Transition: Perimenopausal women had about twice the odds of having a poor overall score when compared with premenopausal women, after adjusting for age.

Early Cancer Cells Change Their Surroundings to Form Tumors: Scientists have demonstrated how cancer cells influence neighboring cells to create a favorable niche for the tumor to grow.

A Better Algorithm for Predicting How Cells Behave: In a preprint published in arXiv, researchers from Altos Labs have described a machine learning algorithm that performs end-to-end prediction of how cells’ gene expression will respond to interventions.

Sleep chart of biological ageing clocks in middle and late life: These findings suggest a cross-organ, multi-omics U-shaped relationship between sleep duration and biological ageing clocks.

Time-restricted feeding improves functional capacity of adipose-derived stem cells with activation of OSK-associated transcriptional programs: TRF is a noninvasive, physiologically safe intervention to restore aged stem cell function and tissue homeostasis during aging.

Pyrroloquinoline quinone and imidazopyrroloquinoline intake diminish mortality risk during midlife and improve muscular dysfunctions with age in mice: This is the first study to demonstrate that PQQ and IPQ supplementation is effective in ameliorating age-related alterations and diminishes mortality risk during midlife in mice.

Can table tennis protect the aging brain? A systematic review and meta-analysis in neurodegenerative diseases: It appears to be a safe, feasible, and potentially effective non-pharmacological intervention for improving cognitive and motor outcomes in individuals with AD, PD, and dementia.

Effect of Nicotinamide Mononucleotide on Retinal Thickness of Older Patients With Diabetes Mellitus: Based on the retinal thickness results, NMN may be efficacious in mitigating age-related alterations in the retina.

Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis: Exercise significantly increases s-Klotho levels, with acute and subacute aerobic sessions benefiting healthy and diseased populations.

Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer’s disease pathology: This study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.

Same Patients, Different Health Care Systems—Revisited. Geriatric Care Models in the U.S., Canada, and Europe: Recommendations emphasize harmonizing geriatric expertise, embedding evidence-based interventions, and fostering cross-system learning to optimize outcomes for older adults.

Methylene blue protects hair follicle stem cells from oxidative and metabolic stress to enhance hair regeneration: Remarkably, pre-treatment with MB protected HFSCs from GLP-1 RA–induced metabolic stress and premature cell death.

Nicotinamide riboside and pterostilbene reduces frequency and severity of undesirable symptoms of the menopause transition: an open-label, pilot clinical trial: This study demonstrates that NRPT is effective in significantly decreasing the frequency and magnitude of undesirable symptoms of the menopause transition.

Mesenchymal drift: A convergent framework for the hallmarks of aging: Partial reprogramming is a potential strategy to restrain or reverse MD and counteract its associated aging hallmarks.

Hypoxia-induced autophagic degradation of HIF-1α attenuates cellular aging and extends mammalian lifespan: These findings define a regulatory axis in which HIF-1α degradation under hypoxia contributes to longevity, and support HATC as a geroprotective strategy to improve healthspan.

Does leisure activity matter for epigenetic aging? Analyses of arts engagement and physical activity in the UK Household Longitudinal Study: These findings position ACEng as a potential contributor to healthy aging at the biological level, supporting its inclusion in public health strategies.

Universal transcriptomic hallmarks of mammalian ageing and mortality: This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.

Bench to bedside: is rapamycin headed for the docTOR?: Rapamycin—or molecules that similarly act to inhibit mTOR—may yet realize the century-old dream of extending healthspan and lifespan with a small molecule.

Plasma glycine decelerates biological aging via the redox-inflammatory axis: A large-scale study modulated by sex and dietary patterns: These results support for precision interventions integrating glycine optimization with anti-inflammatory dietary patterns to extend healthy longevity.

News Nuggets

AI for Practical LongevityForever Healthy Releases AI4L 1.0 for Practical Longevity: AI4L, “AI for Practical Longevity”, is an open-source system that enables anyone to produce rigorous, evidence-based reviews of health and longevity interventions using frontier AI models.

Cyclarity Unveils Oxidized Cholesterol Excretion Data: Cyclarity Therapeutics, Inc. has just unveiled data from a clinical trial of its lead candidate, UDP-003, at the American Heart Association Vascular Discovery Scientific Sessions.

APLMSChina Launches Standardized Physician Education in Longevity: China has launched its first national competency-based education programme in longevity medicine, marking a significant step toward integrating healthy longevity and preventive care into mainstream clinical practice.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Pathway forward

Harvard Publishes a Longevity Report for the General Public

The report, titled “Pathways to Longevity”, introduces several important longevity concepts to the general reader and is another sign that the field is coming of age and entering the mainstream.

People do want to live longer

From time to time, Harvard Health Publishing issues Special Health Reports – consumer-facing, doctor-reviewed guides translating medical research for general readers. Previous reports included topics such as Alzheimer’s and heart disease. This new one, presented to the public earlier this week, is dedicated to healthy longevity. While this report, aimed mostly at curious laypeople and priced at $29, might not reveal a trove of new information to a longevity-savvy reader, it is an unmistakable sign that longevity science and the very idea of extending lifespan and healthspan are finally entering the mainstream.

The report opens by separating the science from the universal wish for a longer life. It quotes a Pew survey that found that 76% of U.S. adults want to reach at least 80 and fully 29% hope to hit 100. The report then notes that, currently, centenarians constitute only about 0.03% of the U.S. population. This shows a significant gap between how long people actually want to live and the current human longevity, suggesting that the idea of life extension appeals to the masses.

The report’s medical editor is Dr. David Barzilai, a longevity physician and consultant who also lectures at Harvard Medical School. Barzilai is a top-tier expert in geroscience and longevity, and this choice lends a lot of credibility to the document.

Hallmarks of aging for dummies

The document indeed introduces the reader to several important longevity-related concepts, such as healthspan vs. lifespan, the concept of biological age, the hallmarks of aging, inflammaging, and so on. Each hallmark gets its own generously sized paragraph, with explanations striking the delicate balance between being overly technical and superficial. It also lists factors that hint at individual longevity and spends some time discussing the notion of “Blue Zones,” casting doubt on the centenarian claims while endorsing the lifestyle lessons.

From the signs and hallmarks of aging, the report moves on to a review of emerging interventions. A framing caveat is repeated throughout: nothing is yet proven to slow, stop, or reverse human aging, and any future therapy will complement, not replace, healthy habits and screening.

“The most important story here is not that Harvard Health Publishing is promising longevity breakthroughs,” Barzilai said. “It’s that a major academic medical institution is introducing the public to the conceptual framework of longevity medicine in an evidence-based way. The report treats lifestyle medicine as the foundation, emerging gerotherapeutics as a serious but still developing clinical frontier, and consumer anti-aging claims as something readers need tools to evaluate critically.”

The medications section includes staples like rapamycin, metformin, and SGLT-2 inhibitors. Importantly, GLP-1-based drugs are mentioned, showing that the notion they have certain anti-aging properties is becoming widely accepted. This section also includes investigational peptides and senolytics.

Under “Other potential interventions,” stem cells, HBOT, sauna, and cold exposure each get a mention. While this list is not meant to be exhaustive, one notable omission is conspicuous: cellular reprogramming. Despite being pursued by top scientists and huge companies like Altos Labs, and having candidates cleared for clinical trials, this crucial part of the longevity landscape is only mentioned in passing in the context of age-related stem cell exhaustion and epigenetic changes.

Be curious, but beware

The report then moves to supplements, with the words “Buyer beware” appearing in the headline. Supplements, the reports rightly notes, are “largely unregulated in the US” and not proven to extend lifespan. The list of supplements, each accompanied by a short overview of the related research, includes crowd pleasers like multivitamins, omega-3, collagen, creatine, and curcumin, among others.

Unsurprisingly, a large section is devoted to healthy dietary habits. While the report says, “there is no single, perfect diet plan everyone should follow,” it recommends consuming more plants and plant protein, and less animal foods and refined carbs. Keto diets get a fair discussion, but a cold shoulder from the authors, while the Mediterranean diet and DASH are highlighted as the best overall options. “The research on time-restricted eating does not fully back up its popularity,” the report says, while noting that it might help people lose weight.

The other two members of the “longevity triad,” exercise and sleep, are covered, too, with cardiorespiratory fitness labeled as “maybe the single best predictor of how long you live.” Many sources highlight aerobic and strength exercise, leaving out the third pillar, balance. Here, it is properly featured. The recommendations include getting at least 7,000 steps daily and grabbing “exercise snacks” – short bouts of physical activity, which, according to recent research, can go a long way.

For alcohol consumption, the report goes with the state-of-the art research, noting: “For decades, many people believed that moderate alcohol intake was good for heart health and overall longevity. In recent years, however, studies have painted a different picture. The current consensus: the less alcohol you drink, the better.”

The promise of longevity medicine

The section “What to know about so-called ‘anti-aging’ programs” directly addresses the rising popularity of longevity clinics and doctors (of which David Barzilai is one) and takes a stance that might seem too conservative for some, but is probably a good place to start for beginners who might have trouble distinguishing the wheat from the chaff (and there’s a lot of chaff out there).

“Longevity medicine is entering a more mature phase,” Barzilai summarizes. “The field is moving beyond isolated claims and toward a framework that asks better questions: What improves function? What delays disease? What changes measurable risk? And what evidence is strong enough to guide clinical decisions?”

For longevity enthusiasts, the report might help to introduce new people into the field as well as serve as proof that longevity science has come of age and is to be taken seriously. “This report is an approachable summary on aging, and the real-world factors which are actionable for personalized and precision health,” said Todd White, managing director of Thalion Initiative, a longevity-focused non-profit. “While not shying away from the possibilities of treatments like peptides which remain, as yet, lightly studied, the report is well grounded.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
DNA modeling

A Better Algorithm for Predicting How Cells Behave

In a preprint published in arXiv, researchers from Altos Labs have described a machine learning algorithm that performs end-to-end prediction of how cells’ gene expression will respond to interventions.

The need for prediction

Simulating biological processes on a computer is an incredibly difficult task. While advanced algorithms such as Google’s AlphaFold have revolutionized protein folding, the complete biochemistry of a cell is orders of magnitude more complex.

One way of getting around this is to simply use live cells. Modern RNA sequencing techniques make it relatively simple to test the effects of genetic perturbations and small-molecule interventions. However, even with this technology, there is still an enormous possibility space, different cell types respond differently, and changing how a cell behaves often requires multiple perturbations at once [1].

Machine learning algorithms, therefore, are intended to predict what sorts of perturbations may be of value to the field in silico, after which these predictions can be tested in vitro before such research can continue on to animals and people. Interestingly, previous work has found that simpler algorithms are largely more useful in broad applications and that removing extra constraints improves these models’ ability to generalize [2].

A flow algorithm with an unusual design choice

To that end, these researchers created PRiMeFlow, an algorithm that works directly within the gene expression space rather than compressing information into lower-dimensional spaces, as previous algorithms had [3]. This flow algorithm uses learned probabilities to transform known information into previously unknown configurations.

The authors note that their architecture of choice, a U-net, is normally considered suboptimal for the task at hand; gene expression ordering is arbitrary, and a U-net is geared towards spatially oriented tasks that involve measuring the relationship between nearby data points. A multi-layer perceptron (MLP) would normally be considered the better option, but ablating their U-net flow data into an MLP only worsened their model’s predictions. They admit that they do not know why this is the case, and they suggest an investigation involving cross-attention mechanisms that might better aggregate information without spatial biases.

Top performance

In its best configuration, PRiMeFlow achieved state-of-the-art performance in three key benchmarks that are part of the PerturBench platform. Two of these benchmarks represent covariate transfer: the model’s ability to predict the impact of perturbations under different conditions, such as cell types that may not have been included in the training data. On the third, which measures combined predictions, it outperformed many other models in all but one metric.

Against a private test set of human embryonic stem cells, PRiMeFlow performed exceptionally well, and this performance was bolstered by further fine-tuning. The best fine-tuned PRiMeFlow model was found to be the closest to in vitro results among all the models on the leaderboard.

The researchers laid out a vision for the future, suggesting that this work could form a foundation of virtual cells, which could theoretically be used to model entire virtual organisms. However, a large variety of computational and algorithmic challenges need to be conquered before such a vision could be made into reality.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Watanabe, K., Panchy, N., Noguchi, S., Suzuki, H., & Hong, T. (2019). Combinatorial perturbation analysis reveals divergent regulations of mesenchymal genes during epithelial-to-mesenchymal transition. NPJ systems biology and applications, 5(1), 21.

[2] Lotfollahi, M., Klimovskaia Susmelj, A., De Donno, C., Hetzel, L., Ji, Y., Ibarra, I. L., … & Theis, F. J. (2023). Predicting cellular responses to complex perturbations in high‐throughput screens. Molecular systems biology, 19(6), MSB202211517.

[3] Klein, D., Fleck, J. S., Bobrovskiy, D., Zimmermann, L., Becker, S., Palma, A., … & Theis, F. J. (2025). CellFlow enables generative single-cell phenotype modeling with flow matching. bioRxiv, 2025-04.

Lung cancer tumor

Early Cancer Cells Change Their Surroundings to Form Tumors

Scientists have demonstrated how cancer cells influence neighboring cells to create a favorable niche for the tumor to grow. This can inform future early-stage cancer therapies [1].

Cancer is a disease of aging. With the exception of childhood cancers, most of which stem from inherited genetic errors, adult cancers tend to occur later in life. It can take years or even decades from an initial mutation for tumors to appear and spread. Most cells with cancerous mutations fail to grow into tumors, but a small number eventually prevails, leading to disease.

One of the key factors that determines the fate of a pre-cancerous cell is its communication with the immediate environment, or stroma, which can either block or support tumor growth [2]. A recent study published in Nature by Erik C. Cardoso and colleagues dissects this relationship in detail in the context of lung adenocarcinoma (LUAD), pointing to the exciting possibility of treating cancers long before they are detected.

Lung cancer often starts with mutations in AT2 cells

The authors focused on LUAD, the most common type of lung cancer, to test how normal lung stem cells become cancer-promoting cells after acquiring cancer-causing mutations. They genetically engineered mice in which a mutation in a critical KRAS gene can be triggered after the animals receive treatment with a drug called tamoxifen. The mutation then only appears in the lungs.

KRAS mutations occur in approximately a third of LUAD cases in patients; however, a single KRAS mutation is not enough to trigger cancer growth, and other changes within the mutant cells and their environment are required [3]. Understanding the exact steps of this process is critical in creating effective treatments.

The first steps in cancer growth are similar to tissue response to injury

Alveolar type II (AT2) cells act as stem cells in the lungs, replacing injured or lost cells of the inner lining, but they also frequently give rise to LUAD. The authors found that when AT2 cells acquire a KRAS mutation, they first enter a transitional “repair-like” state that resembles the lung’s normal response to injury. In this transitional state, AT2 cells carrying mutations begin sending molecular messages that alter nearby fibroblasts and immune cells, gradually creating a microenvironment that supports tumor formation. The authors describe this as the creation of a tumor-permissive niche.

In one of the main findings of the study, the authors identified a signaling molecule called amphiregulin (AREG), which is produced in large amounts by the mutant AT2 cells after they entered the regenerative-like transitional state. AREG activates EGFR signaling in nearby fibroblasts. EGFR is a well-known growth receptor frequently involved in cancer biology.

Non-malignant cells support the tumors and allow them to grow

Fibroblasts are connective tissue cells that normally help maintain lung structure and assist with wound repair. In the mutant environment, however, they are reprogrammed into abnormal fibrotic fibroblasts. These fibroblasts begin expressing genes associated with scarring, wound healing, and extracellular matrix remodeling. Essentially, the lung tissue starts to act as though it has been chronically injured, even though there was no actual wound.

The study also examined immune cells, particularly alveolar macrophages. Macrophages are immune cells that normally help clean debris and fight infection in the lungs. The researchers found that local macrophages are also reprogrammed by the developing tumor environment, adopting a hybrid state with inflammatory and immunosuppressive features. Instead of fighting abnormal cells, these altered macrophages were found to help support tumor development.

Early cancer develops in stages

Interestingly, the sequence of events mattered. First, mutant AT2 cells that have acquired a KRAS mutation enter a regenerative-like state and produce AREG. Second, AREG activates fibroblasts through EGFR signaling. Next, activated fibroblasts remodel the tissue and alter macrophages. Finally, the immune system becomes progressively more supportive of tumor growth, creating a self-reinforcing cycle.

To further test whether this signaling network is truly necessary for tumor formation, the authors blocked different parts of the pathway. When they inhibited EGFR signaling using gefitinib, fibroblast reprogramming was greatly reduced. Macrophage activation was also decreased, and the mutant epithelial cells lost many of their abnormal regenerative features.

They also genetically deleted AREG from the mutant AT2 cells. This had striking effects. Tumor formation dropped significantly, fibrotic fibroblasts were reduced, and immune remodeling was impaired. Without AREG, the mutant cells were much less capable of building a tumor-supportive environment.

Mutant KRAS inhibition breaks up tumor-stoma interactions

Another important aspect of the study was reversibility. The abnormal microenvironment was not permanently fixed at early stages. When the researchers inhibited mutant KRAS signaling using a KRAS-specific inhibitor, many of the abnormal cell states were reversed. Fibroblasts lost their fibrotic characteristics, macrophage remodeling decreased, and epithelial cells regained more normal identities. This suggests that the early tumor-supportive niche remains plastic and potentially treatable before advanced cancer develops.

Similarities in human cancer tissues

The team then investigated whether these findings also apply to human lung cancer. They analyzed single-cell sequencing data from patients with early-stage lung adenocarcinoma. Similar populations of regenerative-like tumor cells were identified in human tumors, and these cells also express high levels of AREG. In addition, human tumors were found to contain fibroblasts with fibrotic gene signatures similar to those seen in mice.

To further validate the results, the researchers created human lung organoids using primary human AT2 cells engineered to express mutant KRAS. These organoids reproduced many of the same features seen in mice. The human mutant cells entered transitional regenerative states, expressed AREG, and induced fibrotic changes in surrounding fibroblasts. Once again, EGFR inhibition blocked these effects.

Key takeaways

Overall, the paper argues that cancer initiation is not simply a matter of mutant cells growing uncontrollably. Instead, the earliest stages of cancer involve active cooperation between mutant epithelial cells, fibroblasts, and immune cells. Mutant cells effectively “educate” their surroundings to support future tumor growth.

The findings are clinically important because they identify a potentially vulnerable window before full cancer develops. Current lung cancer treatments are often given after tumors are already advanced and resistant to therapy. This work suggests that interrupting early communication between mutant cells and their microenvironment — especially the AREG-EGFR signaling pathway — could prevent tumors from establishing supportive niches in the first place.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Cardoso, E. C., Lee, H., England, F. J., Cho, H., Lu, R., Varankar, S. S., … & Lee, J. H. (2026). Early fibrotic niches establish tumour-permissive microenvironments. Nature, 1-11.

[2] Yuan, S., Stewart, K. S., Yang, Y., Abdusselamoglu, M. D., Parigi, S. M., Feinberg, T. Y., … & Fuchs, E. (2022). Ras drives malignancy through stem cell crosstalk with the microenvironment. Nature, 612(7940), 555-563.

[3] Guerra, C., Mijimolle, N., Dhawahir, A., Dubus, P., Barradas, M., Serrano, M., … & Barbacid, M. (2003). Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer cell, 4(2), 111-120.

Heart examination

Cardiovascular Health During the Menopausal Transition

A recent study compared premenopausal, perimenopausal, and postmenopausal women’s cardiovascular health. Perimenopausal women had about twice the odds of having a poor overall score when compared with premenopausal women, after adjusting for age [1].

Menopausal health decline

The menopausal transition, and the associated changes in hormonal levels, especially declining estrogen levels, mark not only the cessation of reproduction but also a general decline in physical and psychosocial health, including a decline in cardiovascular health [2].

In this recent study, the authors focused on changes in women’s cardiovascular health as they go through the menopausal transition. As an indicator of cardiovascular health, they used the American Heart Association’s Life’s Essential 8 (LE8) score across the fertile period (premenopausal stage), the transition stage when menstrual cycles are irregular and hormonal levels fluctuate (perimenopausal stage), and the postmenopausal stage. LE8 is a composite score, ranging from 0 to 100, of eight components that represent various cardiometabolic health-related factors. It includes four self-reported health behaviors (physical activity, diet, smoking status, and sleep duration) and four health factors (blood pressure, blood lipid levels, blood glucose levels, and body mass index [BMI]).

The researchers analyzed data from 9,248 females, aged 18 to 80, who were not pregnant or breastfeeding and who did not have prior cardiovascular disease. This data originated from the National Health and Nutritional Examination Survey cycles 2007 to 2020.

The overall LE8 score worsened, from 72.2 in premenopausal women to 67.3 in perimenopausal women to 64.0 in postmenopausal women, reflecting the effects of chronological and ovarian aging. The diet component scored the lowest, and sleep the highest, across all three groups.

The window of opportunity

An analysis of the results pointed out that perimenopausal women were roughly twice as likely to have a poor LE8 score as premenopausal women were, after adjusting for age. Perimenopausal women had 76% higher chances of poor blood lipid scores and 83% higher chances of poor blood sugar compared to premenopausal women. The same analysis showed that, for postmenopausal women, the likelihood of overall poor LE8 scores appeared to be higher than for premenopausal women, but these results were not statistically significant.

“Our analysis highlights that perimenopause, women’s reproductive transition period to menopause, is the critical time when the increase in cardiovascular risk seems magnified. When we compared women’s LE8 scores to the premenopausal baseline, the perimenopausal group was the first to show a significant jump in the odds of having low heart health,” said Amrita Nayak, M.D., lead author of the study and a research fellow in the division of cardiovascular disease at the University of Alabama at Birmingham.

While perimenopause marks a decline in female cardiometabolic health, it is also an opportunity to intervene. The authors suggest early monitoring of metabolic components to identify cardiometabolic risks and implementing interventions that can reduce the risk of cardiometabolic disease.

“Midlife women should think of the perimenopausal period as a ‘window of opportunity.’ They should be proactive and not wait until they reach menopause to start checking their blood pressure, cholesterol and blood sugar levels,” said Garima Arora, M.D., senior author of the study and a professor of medicine in the division of cardiovascular disease at the University of Alabama at Birmingham.

“Women should talk with their health care team about their reproductive status and any changes they are experiencing. It may be the perfect time to get a baseline for their heart health,” Arora advises.

The major avenue of intervention that the authors see is nutrition, since diet scored poorly across all measured groups. “Nutrition can be a central factor for early and proactive intervention. Focusing on heart-healthy habits early, especially getting regular exercise and following a healthy eating plan like the DASH diet with a focus on lowering salt, can help improve cardiovascular health for perimenopausal women in the years to come,” added Dr. Arora.

Exercise appears to be another promising intervention, as previous studies have suggested that incorporating regular exercise among perimenopausal women helps preserve cardiometabolic health. Such effects were not observed in postmenopausal females. [3,4]

The usual suspect

The authors hypothesize as to why this specific period might be so crucial for female cardiovascular health. The usual suspects in such cases are estrogens, since hormonal changes, especially fluctuations and declines in the levels of estrogens, are one of the main features of menopausal transition [5]. Additionally, estrogens are also known to have cardioprotective effects, including its beneficial impact on lipid profiles, glucose metabolism, and vascular function [6]. Therefore, the researchers hypothesized that perimenopausal fluctuations, rather than menopausal decline in estrogen levels, appear to create a “detrimental and unstable metabolic environment.”

Beyond metabolic effects, the researchers also point to estrogens’ positive effect on the widening of blood vessels, which, when decreased during the perimenopausal transition, can negatively impact blood pressure, further exacerbating cardiovascular health decline.

The next steps

This study agrees with previous reports showing various detrimental metabolic health changes during perimenopause, but it was the first to assess a cardiometabolic score rather than individual elements.

However, this study shows only associations and cannot infer causality. Further longitudinal studies would be needed to investigate it, and such studies should also include a higher number of participants, especially in the perimenopausal stage, to strengthen the evidence.

“Our next step is to follow women over several years to track hormone levels and heart health, which will help clarify the long-term impact of perimenopause and how lifestyle changes can reduce risk,” Arora said. “We hope these findings encourage clinicians to begin screening for high blood pressure, cholesterol and type 2 diabetes earlier in the perimenopausal transition, leading to earlier diagnosis, prevention and intervention at a critical time in women’s lives.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Nayak, A., Pampana, A., Gaonkar, M., Bal, H. S., Yerabolu, K., Shetty, N. S., Vekariya, N., Patel, N. P., Li, P., Arora, P., & Arora, G. (2026). Cardiovascular Health Characterization Using Life’s Essential 8 Score in Perimenopausal Women: An Analysis of the National Health and Nutritional Examination Survey. Journal of the American Heart Association, 15(10), e046898.

[2] Hulteen, R. M., Marlatt, K. L., Allerton, T. D., & Lovre, D. (2023). Detrimental Changes in Health during Menopause: The Role of Physical Activity. International journal of sports medicine, 44(6), 389–396.

[3] Mohr, M., Sjúrðarson, T., Skoradal, M. B., Nordsborg, N. B., & Krustrup, P. (2024). Long-term continuous exercise training counteracts the negative impact of the menopause transition on cardiometabolic health in hypertensive women – a 9-year RCT follow-up. Progress in cardiovascular diseases, 85, 54–62.

[4] Nilsson, S., Henriksson, M., Hammar, M., Berin, E., Lawesson, S. S., Ward, L. J., Li, W., & Holm, A. S. (2024). A 2-year follow-up to a randomized controlled trial on resistance training in postmenopausal women: vasomotor symptoms, quality of life and cardiovascular risk markers. BMC women’s health, 24(1), 511.

[5] Santoro, N., Roeca, C., Peters, B. A., & Neal-Perry, G. (2021). The Menopause Transition: Signs, Symptoms, and Management Options. The Journal of clinical endocrinology and metabolism, 106(1), 1–15.

[6] Miller, V. M., & Duckles, S. P. (2008). Vascular actions of estrogens: functional implications. Pharmacological reviews, 60(2), 210–241.

Brain

Tau Protein Is Crucial for Encoding Long-Term Memory

Scientists have uncovered an unexpected function of the tau protein, which is mostly known for its role in Alzheimer’s and related disorders: helping encode long-term memory. This can inform novel approaches that target tau [1].

In sickness and in health

Tau is a protein found mainly in neurons, where its textbook job is to bind and stabilize microtubules, which provide structural rigidity and help carry cargo inside the axons. In Alzheimer’s disease, frontotemporal dementia, and related disorders collectively known as tauopathies, tau becomes abnormally phosphorylated, detaches from microtubules, and clumps into toxic aggregates. This tracks closely with memory loss.

Despite being central to memory failure in disease, whether tau also plays a role in healthy memory function has been unclear. Previous research seemed to suggest that it mostly does not. For instance, tau-deficient mice learn normally and demonstrate normal short-term recall [2]. Moreover, removing tau protects against cognitive deficits in mouse models of Alzheimer’s [3]. So, the assumption in the field was that tau is not required for memory and only matters for its loss.

A new study, led by Flinders University and published in Nature Communications, challenges this narrative with possible important therapeutic implications. The authors’ hypothesis was that previous studies looked in the wrong place, assessing only short-term memory (hours to days after learning) and ignoring a possible role of tau in long-term memory, which is formed and stored differently.

Thinking long-term

First, the researchers took tau-deficient mice and their tau-competent littermates and put them through three behaviorally distinct memory tasks, testing recall at both recent and remote timepoints. In all three tasks, tau-deficient mice showed normal recent recall but had impaired remote recall. By eliminating alternative explanations, the researchers demonstrated that the defect lies somewhere in the encoding-to-storage process, not in recall machinery or behavioral confounds.

In a switchable model, expressing tau only during the encoding window restored remote memory in tau-deficient mice, while expressing it only during habituation or remote recall did not. Crucially, tau could be completely silenced during the long latency period between learning and testing without harming remote recall, as long as it had been present at encoding. So, tau is required for encoding long-term memories rather than protecting or recalling them.

Tau has numerous phosphorylation sites, and their status defines what the protein does. The team found that phosphorylation at threonine-205 (T205) was the most abundant site, and it was selectively increased by memory encoding.

However, correlation is not causation, so the team created tauT205A mice, in which the threonine at position 205 was swapped for another amino acid, alanine (A). Alanine is structurally similar to threonine but cannot be phosphorylated. These mice showed normal learning and recent recall but impaired remote recall, recapitulating the full tau-knockout phenotype.

Mice lacking p38γ (the kinase that phosphorylates tau at T205) showed the same remote-recall deficit. Effectively, three independent perturbations (no tau, no T205, no T205-kinase) all converged on the same phenotype.

You’ve got an engram!

The question then became “How exactly does T205 facilitate memory creation?” An engram is the physical trace of a specific memory: when you learn something, a subset of neurons, called an ensemble, undergoes lasting changes and becomes the “keeper” of that particular memory. Reactivating exactly those cells can trigger recall. Sparsity and precision are important: a good memory recruits a small, well-defined set of cells and keeps neighboring cells quiet. If unrelated neurons also fire during recall, retrieval fails.

The team labeled the learning ensemble with the fluorescent protein eGFP using an activity-dependent promoter so that only neurons active during encoding get tagged. They separately stained for c-Fos, a protein switched on whenever a neuron is strongly active. By comparing the c-Fos⁺ population to the eGFP-tagged engram, they could measure how precisely activity is confined to the intended ensemble.

Without tau or without T205, engram recruitment (eGFP tagging) was normal but precision collapsed. These mice had excess c-Fos⁺ cells and a lower fraction of double-positive (both belonging to the engram and active) cells, meaning many non-engram neighbors were firing inappropriately. This imprecision persisted at later timepoints and even at remote recall.

Re-expressing T205 tau (but not the T205A mutant) during the encoding window made activity sparser (normal) again, quashing the excessive activation. Importantly, overall network activity, as measured by electroencephalography (EEG), was unchanged, indicating that this is about local selectivity rather than global activity levels.

To prove the effect is cell-autonomous to the active ensemble (not a bystander effect), the team built a vector that expresses tau only in cells active during encoding. Wild-type tau placed specifically in engram cells rescued remote memory and restored sparse c-Fos activity, while the T205A version did neither. The researchers also modeled tauopathies, which are associated with aberrant, aggregation-prone tau [4], by using tauP301S, a disease mutation that causes memory issues when expressed in engram neurons during encoding or remote recall.

The memories are still there

In a crucial experiment, the researchers labeled a fear engram with a light-activated ion channel. This enabled them to trigger those exact cells with light, bypassing natural sensory cues entirely. With the natural cue, tau-deficient mice failed remote recall just like before. However, directly activating the engram with light retrieved the remote memory in both tau-competent and tau-deficient mice. The memory trace was retained in the latter all along; it just could not be reached via the normal activation route.

This work makes it clear that ordinary tau plays an active role in memory formation and cannot be safely depleted as part of therapies. Additionally, at least early in the disease, memories that appear to be lost might be simply inaccessible, and access can possibly be restored.

“Knowing how tau supports the formation and recall of memory could help us better understand what goes wrong in memory loss,” said Associate Professor Ittner, from Flinders’ College of Medicine and Public Health. “Future research will hopefully be able to confirm concepts developed in our study in human memory and show their implications in dementia.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Kosonen, R., Stefanoska, K., Lin, Y., Edwards, S., Prikas, E., Bertz, J., … & Ittner, A. (2026). Tau T205 phosphorylation modulates engram cell recruitment and remote memory in mice. Nature Communications.

[2] Morris, M., Hamto, P., Adame, A., Devidze, N., Masliah, E., & Mucke, L. (2013). Age-appropriate cognition and subtle dopamine-independent motor deficits in aged tau knockout mice. Neurobiology of Aging, 34(6), 1523–1529.

[3] Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007). Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science, 316(5825), 750–754.

[4] Iqbal, K., Liu, F., Gong, C.-X., & Grundke-Iqbal, I. (2010). Tau in Alzheimer disease and related tauopathies. Current Alzheimer Research, 7(8), 656–664.

Omega 3 foods

How Omega-3 Fatty Acids May Alleviate Kidney Disease

Researchers have discovered the role of cellular senescence in the interaction between omega-3 polyunsaturated fatty acids (PUFAs) and chronic kidney disease (CKD).

Previous mixed results

Several clinical trials have found that taking omega-3 PUFAs has benefits for older people. One study found that it reduces the rate of aging according to epigenetic clocks [1], while another found that it lengthens telomeres in people with heart disease [2]. Further studies have found that it has benefits against sarcopenia [3] and cognitive impairment [4].

Studies on its kidney (renal) effects, however, have had mixed results; one study found that it did nothing against renal problems in Type 2 diabetes patients [5], while a meta-analysis found that only fish-derived rather than plant-derived omega-3 PUFAs had benefits against CKD [6]. The authors of this study also found contradictory information relating to the mechanism of action. Therefore, they put together a series of experiments to better determine its effects on senescence and fibrosis in renal cells.

Reduced senescence and better filtration

The researchers began by adminstering omega-3 PUFAs for seven months to wild-type mice beginning at 15 months of age. Compared to the control group, the treated mice had fewer markers of fibrosis and better structuring of tubular epithelial cells (TECs), which normally declines with age. The albumin/creatinine ratio of the treated mice was much more like that of the young mice, collagen deposition was heavily reduced, and the kidneys were better able to perform their basic filtration function. Biomarkers of cellular senescence, including SA-β-gal, were also heavily reduced, and markers of Klotho, which has been linked to aging resistance, were increased. While omega-3 PUFAs did not fully restore these mice’s kidney function to that of young mice, the improvements were broad and substantial.

Similar results were found in a model of CKD induced by alanine as well as in a unilateral ureteral obstruction-induced model of kidney disease.

Turning towards the target

The authors then turned towards FFAR4, the target of omega-3 PUFAs. In human renal samples derived from older people and people with a variety of kidney diseases, FFAR4 was markedly reduced compared to samples derived from younger people.

Another mouse experiment confirmed FFAR4’s effects. Compared to a control group, older mice that had FFAR4 deleted from their TECs had considerably worse outcomes: they excreted more protein in their urine and had more signs of pathological injury along with increased cellular senescence markers, including increases in lipofuscin and SA-β-gal. In the adenine-induced and obstruction-induced models of kidney disease, the FFAR4 TEC-knockout mice had even worse outcomes as well.

The researchers then linked FFAR4 in TECs to renal fibrosis. Previous work had found that senescent TECs secrete factors that cause renal fibrosis [7]. A single-cell RNA sequencing analysis found a population of fibroblasts that was particularly susceptible to this paracrine action in cases of CKD. A further in vitro experiment discovered the interaction pathway: TGF-β1, which induces senescence in TECs, caused them to secrete factors that led to increased fibrosis in fibroblasts. However, administering a FFAR4 agonist reversed the effects of TGF-β1. Using hydrogen peroxide instead of TGF-β1 as the senescence driver yielded similar results, and knocking down FFAR4 in senescent TECs made the paracrine effects worse.

FFAR4 was also found to have beneficial effects on PPARγ, which promotes Klotho expression. TGF-β1 also reduced PPARγ expression, which was similarly restored by an FFAR4 agonist. Older mice express less 15-d PGJ2, which activates PPARγ, than young mice, but administering omega-3 PUFAs substantially increased the expression of 15-d PGJ2 to levels far higher than those of young mice.

This research did not touch upon CKD in the context of diabetes, and it did not precisely outline the effects of omega-3 PUFAs on the kidneys of mice as they age. However, it provides a mechanistic explanation of how omega-3 PUFAs may improve kidney function in older people, and it paves the way for the potential development of future treatments that target FFAR4 in TECs in order to alleviate kidney disease in older people.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Bischoff-Ferrari, H. A., Gängler, S., Wieczorek, M., Belsky, D. W., Ryan, J., Kressig, R. W., … & Horvath, S. (2025). Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial. Nature Aging, 5(3), 376-385.

[2] Farzaneh-Far, R., Lin, J., Epel, E. S., Harris, W. S., Blackburn, E. H., & Whooley, M. A. (2010). Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. Jama, 303(3), 250-257.

[3] Pan, D., Yang, L., Yang, X., Xu, D., Wang, S., Gao, H., … & Sun, G. (2024). Potential nutritional strategies to prevent and reverse sarcopenia in aging process: Role of fish oil-derived ω-3 polyunsaturated fatty acids, wheat oligopeptide and their combined intervention. Journal of Advanced Research, 57, 77-91.

[4] Zhang, X., Yuan, T., Chen, X., Liu, X., Hu, J., & Liu, Z. (2024). Effects of DHA on cognitive dysfunction in aging and Alzheimer’s disease: The mediating roles of ApoE. Progress in Lipid Research, 93, 101256.

[5] de Boer, I. H., Zelnick, L. R., Ruzinski, J., Friedenberg, G., Duszlak, J., Bubes, V. Y., … & Manson, J. E. (2019). Effect of vitamin D and omega-3 fatty acid supplementation on kidney function in patients with type 2 diabetes: a randomized clinical trial. Jama, 322(19), 1899-1909.

[6] Ong, K. L., Marklund, M., Huang, L., Rye, K. A., Hui, N., Pan, X. F., … & Wu, J. H. (2023). Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. bmj, 380.

[7] Li, L., Fu, H., & Liu, Y. (2022). The fibrogenic niche in kidney fibrosis: components and mechanisms. Nature Reviews Nephrology, 18(9), 545-557.

Mitochondrial membrane

Mitochondrial Aging Linked to Losing Crucial Membrane Lipid

Scientists have found that the levels of phosphatidylcholine, the most abundant lipid in mitochondrial membranes, decline with age, driving mitochondrial aging in worms and possibly humans. Supplementing the lipid helped in an in vitro experiment [1].

What drives mitochondrial aging?

Mitochondria are the cell’s energy-generating organelles, and their decline is a hallmark of aging [2]. While scientists know a lot about mitochondrial conditions caused by genetics, what is far less understood is what drives mitochondrial deterioration during “ordinary” aging, in the absence of any inherited defect. The authors of a new study from Leibniz Institute on Aging, published in Nature Communications, set out to find the “natural” drivers of mitochondrial aging that would be realistic intervention points, especially in later life.

Instead of studying animals whose mitochondria fail and contribute to aging, the researchers went in the opposite direction and decided to study two exceptions to the rule: long-lived mutant strains of the nematode worm C. elegans (clk-1 and isp-1) that have permanently impaired mitochondria yet live longer than normal worms. If these animals thrive despite lifelong mitochondrial dysfunction, they must have built-in protections.

The worms that live longer with bad mitochondria

First, the team ran longitudinal proteomics on normal worms and the two long-lived mutants. Two findings came out. First, in normal aging, mitochondrial protein changes appear relatively late in life, which hints at a possibility of late-stage interference. Second, longer-lived strains had fewer proteins altered by aging, and the protective adaptations shared by the two mutants were mostly rooted in non-mitochondrial genes.

The authors looked for individual proteins that drop sharply during normal aging but stay stable in the protected mutants. The top hit was S-adenosylmethionine synthetase (SAMS-1). It was strongly and progressively downregulated with age in WT worms but maintained in both long-lived mutants.

Knocking down sams-1 actually extended lifespan in normal worms while shortening the lifespan of both long-lived mutants, as if its effect on longevity flipped depending on mitochondrial health. When mitochondria are young and functional, losing sams-1 seems to be beneficial, which is consistent with prior literature [3]. However, when mitochondria are already compromised (in mutants or aged worms), sams-1 becomes crucial, and its loss is harmful.

Mitochondria in healthy, vigorous cells tend to form networks, which are good at generating and distributing energy across the cell, allowing the cell to adapt to changing energy demands. “You can imagine the whole system as a finely branched power grid that becomes increasingly damaged with age: connections break down and currents stall,” explained Dr. Ermolaeva, the study’s lead author. “Although energy production continues, it becomes less efficient and sustainable, and energy can no longer be distributed flexibly.”

sams-1 knockdown severely fragmented the mitochondrial network and triggered mitochondrial stress. “We were surprised ourselves by how strongly this molecule influences the structure, connectivity, and function of mitochondria,” says Dr. Tetiana Poliezhaieva, the study’s first author.

The most abundant mitochondrial membrane lipid is the key

S-adenosylmethionine is involved in multiple processes, including the synthesis of phosphatidylcholine (PC), the dominant lipid in mitochondrial membranes. PC is important for the membrane fluidity that fusion requires.

PMT-1 and PMT-2 are two central enzymes in PC production. Knocking down pmt-1 reproduced the mitochondrial fragmentation seen with sams-1 knockdown. Knockdown of either pmt-1 or pmt-2 resembled the sams-1 longevity pattern (extending WT lifespan but shortening the mutants’ lifespan), suggesting that all three genes share a role here via PC production.

Dietary PC supplementation reversed the mitochondrial fragmentation and the reduced body size in both pmt-1 and sams-1 knockdowns. Since PC’s instability requires dissolving it in a mildly toxic solvent, the researchers also tried supplementing PC’s precursor, choline. This rescued the morphology and body-size defects of sams-1, pmt-1, and pmt-2 knockdowns and restored PC synthesis.

Human data offers support

To see if their findings are generalizable, the team turned to existing human data. In the GTEx human transcriptomics database, PEMT, the human functional analog of PMT-1/2, trended downward with age across several tissues, especially in high-lipid tissues like fat and ovary. In UK Biobank data, total PC in plasma declined with age in older men, and relative PC (normalized to total fatty acids) dropped sharply in women after roughly menopausal age – this is notable because menopause is linked to declining mitochondrial function in women [4]. PC levels also correlated favorably with markers of healthy aging, such as lower comorbidity index, faster walking pace, and better memory.

The researchers also performed an in vitro rescue experiment. Skin fibroblasts exposed to metformin, which inhibits mitochondrial complex I, were protected by choline. “Our work shows that both mitochondrial aging and broader systemic aging are, at least in part, modifiable,” summarizes Dr. Ermolaeva. “If we understand the underlying processes, we may be able to take targeted countermeasures.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Poliezhaieva, T., Li, Y., Chaudhari, P. S., Isildak, U., Alonso-Pernas, P., Valentim, I. S., … & Ermolaeva, M. A. (2026). Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging. Nature Communications, 17(1), 3589.

[2] Amorim, J. A., Coppotelli, G., Rolo, A. P., Palmeira, C. M., Ross, J. M., & Sinclair, D. A. (2022). Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nature Reviews Endocrinology, 18(4), 243–258.

[3] Lim, C. Y., Lin, S., Kennon-McGill, P., … (2023). SAMS-1 coordinates HLH-30/TFEB and PHA-4/FOXA activities through histone methylation to mediate dietary restriction-induced autophagy and longevity. Autophagy, 19(1), 224–240.

[4] Velarde, M. C. (2013). Pleiotropic actions of estrogen: A mitochondrial matter. Physiological Genomics, 45(3), 106–109.

Cataracts

How an Oxidative Stress Regulator Makes Cataracts Worse

Researchers have outlined a key receptor and protein involved in the formation of cataracts, paving the way for potential treatments targeting them.

Oxidative stress and cataracts are closely related

Cataracts, which cloud the lenses of the eye, are one of the most common sources of age-related vision loss [1]. While they are treatable through surgery and artificial lens replacement, regenerative medicine is required to avoid surgical complications [2].

The aging of of lens epithelial cells (LECs), which normally surround the lens and keep it transparent [3], can cause cataracts as the cells suffer oxidative stress, protein misfolding, mishandling of calcium ions, and epigenetic alterations [4]. This also leads to these cells’ senescence and the iron-related cellular death known as ferroptosis [5].

Retinoic acid receptor-associated orphan receptors (RORs), most notably RORA, have been previously investigated in the context of eye diseases [6], including dry age-related macular degeneration [7] and oxygen-induced retinopathy [8]. RORA seems to play contradictory roles in different tissues: studies found that it is beneficial against oxidative stress in heart disease [9] and in Parkinson’s [10], but in wet AMD, it has been found to be harmful [11]. Therefore, these researchers decided to take a look at how RORA interacts with LECs.

Upregulation of this regulator worsens oxidative stress

These researchers created a model of cataracts by injecting rats with sodium selenite, a compound known to cause this condition. As expected, the injected rats suffered from severe lens damage a week later, including small voids and altered structure. This was accompanied by increased oxidative stress in LECs, increases in age-related biomarkers such as SA-β-gal, and markers of cellular death by apoptosis. RORA was similarly upregulated as well. Similar results were found in donated human tissues: RORs, most notably RORA, were upregulated in LECs that surrounded cataract lenses.

The researchers then turned to an in vitro experiment, culturing LECs in a medium rich in hydrogen peroxide in order to induce oxidative damage. As expected, markers of cellular senescence and apoptosis were increased in these cells along with oxidative stress, and RORA was increased as well.

However, this only reveals an association and does not prove that RORA has any kind of causative effect. To ascertain that, the researchers used one population of cells with RORA silenced and another population with RORA upregulated. RORA was found to be harmful rather than protective against oxidative stress: silencing it led to diminished stress markers, including markers related to apoptosis and cellular senescence. On the other hand, upregulating RORA in these cells increased these markers.

A downstream protein causes the damage

With the KEGG RNA database as their initial clue, the researchers found that the gene that encodes for prion protein (PRNP) was upregulated as a downstream consequence of RORA upregulation, a finding that was corroborated with PRNP upregulation in the donated cataract tissue, the in vitro cells exposed to hydrogen peroxide, and the rat model of cataracts. Another investigation using the JASPER database found that RORA has binding sites that directly led to increased expression of PRNP.

In vitro work found that PRNP was directly responsible for the increased oxidative stress associated with RORA in cells exposed to hydrogen peroxide. Upregulating PRNP neutralized the benefits of silencing RORA, increasing the associated senescence- and apoptosis-related biomarkers. This was confirmed by a rat experiment: silencing RORA in rats exposed to sodium selenite reduced their oxidative stress markers and cataract sizes, but upregulating PRNP reversed this effect.

RORA PRNP rats

These researchers note the difficulties involved in targeting RORA itself, stating that the “efficient and targeted delivery of RORA inhibitors to lens tissue remains the core bottleneck limiting clinical translation of this strategy.” However, molecules that target PRNP or the RORA-PRNP axis, preventing RORA from activating PRNP, may be more feasible as clinical treatments. Future work will determine if such strategies can stop cataracts before they start and reduce the need for surgery.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Liu, Y. C., Wilkins, M., Kim, T., Malyugin, B., & Mehta, J. S. (2017). Cataracts. The Lancet, 390(10094), 600-612.

[2] Lin, H., Ouyang, H., Zhu, J., Huang, S., Liu, Z., Chen, S., … & Liu, Y. (2016). Lens regeneration using endogenous stem cells with gain of visual function. Nature, 531(7594), 323-328.

[3] Mathias, R. T., White, T. W., & Gong, X. (2010). Lens gap junctions in growth, differentiation, and homeostasis. Physiological reviews, 90(1), 179-206.

[4] Periyasamy, P., & Shinohara, T. (2017). Age-related cataracts: Role of unfolded protein response, Ca2+ mobilization, epigenetic DNA modifications, and loss of Nrf2/Keap1 dependent cytoprotection. Progress in retinal and eye research, 60, 1-19.

[5] Wei, Z., Hao, C., Huangfu, J., Srinivasagan, R., Zhang, X., & Fan, X. (2021). Aging lens epithelium is susceptible to ferroptosis. Free Radical Biology and Medicine, 167, 94-108.

[6] Yemanyi, F., Bora, K., Blomfield, A. K., & Chen, J. (2023). Retinoic acid receptor-related orphan receptors (RORs) in eye development and disease. Retinal Degenerative Diseases XIX: Mechanisms and Experimental Therapy, 327-332.

[7] Akula, M., McNamee, S. M., Love, Z., Nasraty, N., Chan, N. P. M., Whalen, M., … & Haider, N. B. (2024). Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD. Gene Therapy, 31(7), 413-421.

[8] Sun, Y. E., Liu, C. H., Wang, Z., Meng, S. S., Burnim, S. B., SanGiovanni, J. P., … & Chen, J. (2017). RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. The FASEB Journal, 31(10), 4492-4502.

[9] Xu, L., Su, Y., Zhao, Y., Sheng, X., Tong, R., Ying, X., … & Pu, J. (2019). Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling. Journal of Pineal Research, 67(2), e12579.

[10] Al-Zaid, F. S., Hurley, M. J., Dexter, D. T., & Gillies, G. E. (2023). Neuroprotective role for RORA in Parkinson’s disease revealed by analysis of post-mortem brain and a dopaminergic cell line. npj Parkinson’s Disease, 9(1), 119.

[11] Schaumberg, D. A., Chasman, D., Morrison, M. A., Adams, S. M., Guo, Q., Hunter, D. J., … & DeAngelis, M. M. (2010). Prospective study of common variants in the retinoic acid receptor–related orphan receptor α gene and risk of neovascular age-related macular degeneration. Archives of ophthalmology, 128(11), 1462-1471.

Identifying DNA

Untangling Cellular Senescence at Its Roots

In Aging Cell, researchers have described the differences between primary and secondary senescent cells, comparing radiation-induced senescence to senescence induced by the senescence-associated secretory phenotype (SASP).

Heterogeneity on top of heterogeneity

It is well-known that senescent cells are highly heterogenous [1]; senescent cells from one tissue may behave differently from senescent cells in another tissue, and cells that exhibit senescent traits as the result of injury are different from cells that have been driven senescent by aging. This makes dealing with senescent cells potentially even more difficult than cancer; while removing cancer cells is universally beneficial, the same is not true of senescent cells. Similarly to cancer, however, different treatments work against different senescent cell populations [2].

One key difference involves how the cells became senescent. Replicative senescence due to telomere attrition (the “Hayflick limit”) is probably the most well-known of these, but cells can also be induced to senescence through toxic exposure or, as was done in this study, intense radiation; this fact is a core part of radiotherapy’s effectiveness as a cancer treatment. Cells driven to senescence through such methods are primary senescent cells.

Senescence can also be induced through exposure to other senescent cells’ SASP, which makes them secondary senescent cells [3]. Previous work has found that these cells behave differently from primary senescent cells, including in the way they secrete their own SASP [4]. However, the molecular biology behind these different cell types has not been fully explored in detail.

Different trajectories in the same group

These researchers used single-cell RNA sequencing (sc-RNAseq) to investigate kidney (renal) cells, first comparing a control group of quiescent cells to cells that were driven senescent through powerful radiation. The primary senescent cells exhibited all of the standard features of senescence: the telltale biomarker SA-β-gal, upregulated key senescence-associated genes, and increased expression of key inflammatory factors that make up the SASP. However, not all of the targeted cells became fully senescent.

An algorithm was able to cluster the RNA expression of these cells into two clusters associated with nonsenescence, four clusters associated with an intermediate state of senescence, and three more associated with complete senescence: C5, C6, and C8. However, even these three primary senescent groups were heterogenous: C5 strongly expressed development-related genes, while C6 and C8 each expressed stress response genes and genes related to death by apoptosis.

The researchers then used another algorithm, Slingshot, to investigate how these different types of cells had progressed towards senescence. C5 exhibited DNA damage and possible cancer, C6 exhibited increased ribosomal activity and nucleolar stress, and C8 had exhibited genes related to the SASP. The researchers described the C8 group as “consistent with a terminal senescent program characterized by elevated SASP activity and tissue remodeling features”.

Culturing cells in the SASP

This experiment was performed again, except instead of using radiation to induce senescence, the researchers cultured cells in a medium rich in SASP factors. Cells driven secondarily senescent this way exhibited the same standard senescence features that the primary senescent cells did: the increase in SA-β-gal, the decrease in proliferation, and the induction of their own SASP were all present.

However, their gene expression was not the same. Some cells that did not become senescent resisted the SASP’s effects entirely, while other non-senescent cells exhibited increased DNA damage repair markers. The secondary senescent cells exhibited fewer cancer-related genes and more DNA damage repair than the primary senescent cells did. Slingshot revealed that, while some of the final trajectories were similar to those of primary senescent cells, the stresses induced by the SASP were not the same as those induced by radiation. Notably, some cells in the secondary senescent group expressed a terminal trajectory related to hypoxia, which did not occur in the primary senescent group.

Perhaps most critically, the primary senescent cells were more likely to exhibit ECM remodeling cells as they became senescent, which the researchers noted may increase fibrosis, while the secondary senescent cells were more likely to exhibit genes related to inflammation.

This study had some key limitations. The primary senescent cells were only driven that way through radiation rather than telomere attrition or doxorubicin, which may have changed their gene expression. Only renal cells were used in this study; other cells, such as skin cells or bone marrow cells, may have exhibited different properties. However, this study provides other researchers with crucial information in dealing with different senescent cell populations and highlights the need for specific targeting when dealing with these necessary but potentially dangerous cells.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: insights at the single-cell level. Trends in cell biology, 33(1), 9-17.

[2] Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021). Strategies for targeting senescent cells in human disease. Nature aging, 1(10), 870-879.

[3] Jeon, O. H., Mehdipour, M., Gil, T. H., Kang, M., Aguirre, N. W., Robinson, Z. R., … & Conboy, I. M. (2022). Systemic induction of senescence in young mice after single heterochronic blood exchange. Nature Metabolism, 4(8), 995-1006.

[4] Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., … & Gil, J. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature cell biology, 15(8), 978-990.

APLMS

China Launches Standardized Physician Education in Longevity

Beijing, China — In response to the growing healthcare demands of a rapidly ageing population, China has launched its first national competency-based education programme in longevity medicine, marking a significant step toward integrating healthy longevity and preventive care into mainstream clinical practice. The initiative was jointly developed by the China Non-public Medical Institutions Association and the Asia-Pacific Longevity Medicine Society (APLMS).

The newly introduced Standardized Training Curriculum for Physicians in Longevity Medicine establishes a structured educational framework for this emerging interdisciplinary field. The programme aims to cultivate a new generation of physicians capable of addressing ageing-related health challenges through evidence-based, preventive, and patient-centred approaches aligned with the national Healthy China 2030 strategy.

China Longevity Medicine

Unlike traditional disease-focused healthcare models, longevity medicine emphasises extending healthspan — the years lived in good health — rather than merely increasing lifespan. The curriculum integrates ageing biology, management of age-related multimorbidity, nutrition and exercise interventions, traditional Chinese medicine, psychosocial health, digital medicine, AI-assisted clinical decision-making, and real-world evidence into physician training.

The programme is designed for licensed physicians in internal medicine, general practice, geriatrics, cardiology, endocrinology, rehabilitation, and related specialties. Participants complete structured coursework, case-based learning, supervised clinical practice, and competency assessments before receiving certification in longevity medicine.

According to Dr Tim Shi, President of the Asia-Pacific Longevity Medicine Society (APLMS) and programme lead, longevity medicine represents a new clinical paradigm grounded in gerscience, comprehensive chronic disease management, and early risk prediction.

“As populations age globally, healthcare systems must transition from reactive disease treatment toward proactive healthspan management,” said Dr Shi. “This initiative is designed to help physicians identify opportunities for earlier intervention, preserve functional capacity, and improve quality of life throughout the ageing process.”

The curriculum also places strong emphasis on medical ethics, regulatory compliance, risk communication, and evidence-based practice. Given the rapid expansion of geroscience-guided therapeutics, nutritional supplementation, regenerative medicine, and digital health technologies, the programme highlights the importance of scientific rigour, patient safety, and responsible clinical implementation.

Key areas of training include:

  • Ageing biology and biomarkers
  • AI-assisted clinical decision support
  • Biological age assessment and digital monitoring
  • Cardiometabolic disease prevention
  • Cognitive health and brain ageing
  • Osteoporosis and sarcopenia management
  • Personalised lifestyle and nutritional interventions
  • Traditional Chinese medicine and wellbeing
  • Real-world evidence and N-of-1 clinical methodologies

The initiative is regarded as one of the earliest national-level efforts to build system-wide capacity in longevity medicine within a rapidly ageing middle-income country. Organisers believe the programme could serve as a reference model for other healthcare systems seeking scalable strategies to promote healthy ageing, reduce long-term healthcare burdens, and strengthen preventive healthcare delivery.

As China moves toward becoming a longevity society, the programme reflects a broader transformation in healthcare priorities — from treating disease after onset to maintaining health, resilience, and functional wellbeing across the lifespan.

China Longevity Medicine 2
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Targeting cancer

CRISPR-Based System Targets RNA and Kills Cells on Demand

Scientists have devised a CRISPR-based tool that can kill cells carrying a specific strand of RNA. The tested targets include cancerous and virus-infected cells [1].

Targeted assassination of cells

CRISPR-based systems work by cutting or changing DNA at a particular spot, an ability that can be used to fix dangerous mutations, such as in the famous case of Baby KJ [2]. However, sometimes you need to kill cells with specific features instead of fixing them. Current tools can target proteins inside and on the cell, but they often struggle when the relevant feature is a non-coding RNA, a spot mutation, or a viral transcript in an infected cell [3]. A method that reads a cell’s RNA and decides whether to kill it would unlock interventions not presently possible.

Can CRISPR-based systems help? They can recognize a particular DNA or RNA sequence and cut the molecule, but in itself, this won’t do much: destroying a single RNA transcript would have little effect, and cutting DNA at one spot would only make the cell repair the cut. But hope is not lost: in a new study, published in Nature, scientists from Utah State University offer an elegant solution.

The enzyme that goes wild

The authors had previously discovered a new enzyme called Cas12a2 that behaves unusually in bacteria. When its guide RNA finds a matching RNA target, Cas12a2 doesn’t just cut that one molecule. Instead, it “goes berserk,” indiscriminately chopping up any double-stranded DNA it can find, including the cell’s own. In bacteria, this works spectacularly, leading to cellular death. However, eukaryotic cells have much more robust DNA repair mechanisms. Going into this new study, the researchers wanted to know whether their invention could stay ahead of these mechanisms and kill the cell before it can patch itself up.

First, the team delivered Cas12a2 plus a guide RNA targeting the ADE2 gene transcript into baker’s yeast, Saccharomyces cerevisiae. ADE2 is a non-essential gene whose disruption turns yeast colonies red. Cas12a2 reduced surviving yeast colonies by 134-fold.

As a control, the researchers used FnCas12a, a conventional DNA-cutting nuclease that targets the same site but only that site, without going berserk on all the cell’s DNA. The team provided the yeast cells with a “repair template” that they could use to repair the break at the price of silencing the gene. The control enzyme only reduced colonies four-fold, and the remaining colonies turned red, showing that the yeast indeed had successfully deployed its DNA repair mechanisms to recover.

Next, the authors tested whether Cas12a2’s cell-killing abilities would translate into human cells, which have even more elaborate repair machinery than yeast, by targeting HeLa cells (a human cervical cancer cell line). Cells that had received the construct via electroporation, in which electric impulses cause the cells in the dish to open pores in their membranes, failed to proliferate and shrank in number.

The authors then broadened the test to six different transcripts (KRAS, EGFR, TP53, CD8A, MALAT1, GAPDH) across four cancer cell lines (melanoma, lung, head-and-neck cancers). Killing worked across cell types and even on poorly expressed transcripts. This time, they delivered the system via lipid nanoparticles (LNPs), the same delivery platform used for mRNA vaccines, which may make future therapeutic administration easier.

After confirming that DNA shredding and cell death indeed happens, the team tackled the important question of off-target activation: does the enzyme ever get activated by an RNA that wasn’t the intended target? If yes, it would kill cells that shouldn’t be killed. They found that Cas12a2 targeting transcripts that don’t exist in human cells does not cause DNA shredding or cell death, and that their tool is very sensitive to mismatches; even if cells carry RNA fragments that only slightly differ from the template, Cas12a2 does not mistake them for its target.

The possible applications are many

Finally, it was time to try three possible applications. First, the team targeted high-risk human papillomavirus (HPV), which drives cervical and head-and-neck cancer. HPV-positive head-and-neck cancer tissue from a real patient was grafted into immunodeficient mice. Once tumors reached about 150 mm³, the authors delivered Cas12a2 directly into the tumors, significantly reducing tumor growth.

The second application involved gene editing, which is often inefficient; a million cells can be transfected but only a small fraction actually gets the desired edit. What if we could kill the unedited cells, leaving an enriched population of edited ones? Apparently, Cas12a2 targeting the unedited sequence did just that.

The third application was the most challenging. Many cancers are driven by single-base mutations, such as KRAS G12C, which triggers unbridled cell growth. About 13% of lung adenocarcinomas carry this mutation. An FDA-approved drug, sotorasib, targets KRAS G12C, but tumors often evolve resistance to it. The authors designed three guiding templates, but only one was able to target the mutation and not the wild-type gene.

The killing rate was not perfect, especially in cells heterozygous for the mutation (when one chromosome carries the mutation, and the other one carries the wild-type gene). Cas12a2 depleted these cells by 50%, while sotorasib killed 65%. However, the combination of the two therapies produced a synergistic effect, killing more than 85% of the cells. In cancer, scientists strive to get the perfect result, since a few surviving cells can “rebuild” the tumor, but even these results are highly encouraging as a proof of concept.

“Because Cas12a2 can be programmed with a guide RNA to target any RNA sequence, and it shows little to no off-targeting, we believe we have discovered a way to selectively kill cells across all of biology,” said Utah State University biochemist Ryan Jackso, a leading author. “We show it can be used to enrich for gene editing, and to selectively kill cells harboring virus genes, and to kill cells with acquired mutations. We envision this technology will transform science, agriculture and medicine in ways previously unavailable.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Scholz, P., Thompson, J., Crosby, K. T., Fauth, T., Krah, N. M., Schlauderaff, G., … & Liu, Y. (2026). RNA-triggered cell killing with CRISPR–Cas12a2. Nature, 1-10.

[2] Musunuru, K., Grandinette, S. A., Wang, X., Hudson, T. R., Briseno, K., Berry, A. M., … & Ahrens-Nicklas, R. C. (2025). Patient-specific in vivo gene editing to treat a rare genetic disease. New England Journal of Medicine, 392(22), 2235-2243.

[3] Coan, M., Haefliger, S., Ounzain, S., & Johnson, R. (2024). Targeting and engineering long non-coding RNAs for cancer therapy Nature Reviews Genetics, 25(8), 578-595.

Reason Interview

Developing a Drug To Reverse Heart Disease

We have spoken with Reason from Repair Biotechnologies about his company’s lead candidate, REP-0004, a drug targeting the liver to reduce excess intracellular free cholesterol. The FDA has granted Repair Bio an orphan drug indication, and the company is aiming for clinical trials by mid-2027. Our conversation also touches on the regulatory challenges and the broader implications of rejuvenation therapies.

So let’s get straight into the lead candidate. REP-0003, can you give us the quick, layman’s version on how that works?

Firstly, it’s actually REP-0004 now that is the lead candidate. We updated the sequence, but these two drugs are both very similar. They are lipid nanoparticles that encapsulate messenger RNA and then deliver it directly to the liver and nowhere else in the body. It goes to the liver via the normal mechanisms of lipid nanoparticle delivery. The particles are sized to pass through the blood vessel walls for glands like the liver, and the liver is the usual destination for things that are injected intravenously anyway.

Secondly, there’s a ligand on the surface that only interacts with receptors present on hepatocytes, so that then delivers the mRNA into the cells through the receptor-mediated endocytosis; the mRNA escapes the endosome into the cell, where it is processed into a protein. That protein is just a selection of human proteins that are not normally expressed together in any cell, and together, they very selectively, only break down excess intracellular free cholesterol. By free cholesterol, I mean unmodified cholesterol.

This then produces a variety of benefits to your liver, because free cholesterol is toxic and it serves no useful purpose if you have too much of it inside a cell. Normally, a cell will attempt to take that free cholesterol and keep just a little bit of it, and the rest of it gets esterified into lipid droplets or put into the cell membrane or handed off in some way. But, if you get fat or you get old, in both cases, this process stops working as well, and you have too much free cholesterol.

I should emphasize this really isn’t just a problem of obesity. You can have thin people with excessive free cholesterol in their liver and elsewhere in their bodies.

Now, when you reduce free cholesterol in the liver, it kicks it back into working properly, and also makes it feel like it’s in a cholesterol deficit, even if it isn’t. So, it will try to pull as much cholesterol back from the rest of the body as it can. Various mechanisms of homeostasis will dial up reverse cholesterol transport, and you drag back free cholesterol from the rest of the body to the liver, where it then gets intercepted by the protein and broken down.

You get this feedback loop that operates for the few days that the protein is present in the body as a result of an mRNA therapy, and the outcome is a draining of this excess free cholesterol everywhere, not just the liver, and that reduces inflammation. It improves tissue function throughout the body, outside the brain, at least because the brain has its own fairly distinct cholesterol metabolism.

The two outcomes of greatest interest at the moment are, firstly, you get a dramatic regression of atherosclerotic plaque very rapidly, and secondly, you get a reversal of liver disease, such as metabolic dysfunction and associated hepatitis. You also get a reduction in fibrosis. It happens very rapidly and dramatically, and that is how the drug works.

That’s quite a knock-on effect from just targeting a single organ. What about 7-Ketocholesterol (7KC), the form of oxidized cholesterol that makes up much of the soft plaques. Would it have any effect on that?

Yes, we break down most forms of cholesterol, provided they’re inside the cell. We don’t touch cholesterol directly outside the cell, or indeed, outside the liver. In the case of this particular drug, of course, we can make other drugs to deliver this to other parts of the body. We’re about to start working on neurodegenerative conditions. And there’s certainly other options for other conditions like lung disease, for example, anyway, so yes, we can break down almost all forms of modified cholesterol.

If you’re familiar with lipid biology, cholesterol is sort of in the middle of this huge chart of molecules, hundreds of them that are all vaguely similar in structure and are either cholesterol plus some stuff or cholesterol minus some stuff, or can be processed from cholesterol or to cholesterol. There’s a lot of them, and a lot of these are problematic molecules, a lot of the oxidized ones. Cells do not like them, and getting rid of them is generally a good idea.

We haven’t looked specifically at what we do to 7KC because that’s not necessary for any of the parts we take into the clinic, but we know that we do break it down. For example, one could go run studies in a dish and load up cells with your oxidized cholesterol of choice, and we’ve done this for acetylated cholesterol and oxidized LDL and other such things, and then look at the outcome. The outcome is that we get rid of this stuff, and the cell is happier as a result.

Presumably, this cholesterol that’s pulled in would then ultimately be excreted in the urine and to be safely disposed of?

In fact, the primary catabolite produced by our fusion protein as a result of its interaction with cholesterol is actually a generally recognized as safe molecule, and it stays in the body for only a short time before it’s removed.

In January last year, your company announced positive feedback from a pre-IND meeting with the FDA, potentially paving the way for future Phase 1 studies. How’s that going?

Yeah, everything between then, now, and those Phase 1 studies are roughly GMP, manufacturing, development, and IND-enabling studies and toxicity studies stuck on the end of that. We have a rather long Good Manufacturing Practice development process.

Unfortunately, there was a big Request for Proposal (RFP) at the start. For part of it, we have to do one of the lipids that’s in the lipid nanoparticles. Then we have to do the drug itself. It’s a two-stage dance and it’s going quite well, but we are sort of midway through the whole process. Really, that means we are a few months into getting the process development underway. There’s nothing revolutionary happening here, it’s just work, but it has to be done.

Lipid nanoparticles are extremely cutting-edge. They are quite different to other ways of delivering things. We saw with the RNA approach with the COVID vaccine, how effective that was and how quickly they can scale things if they need to.

Yes, let’s hope they get more receptive to rejuvenation and then we might see a catalyst where everything starts to move a bit faster. How receptive has the FDA been to this approach?

They like it. They looked at our materials for the pre-IND and said, “Yes, we agree. Go do this.” No, they didn’t note any meaningful objections, just the usual small feedback. They gave us an orphan drug indication, and they don’t hand that out like candy. That’s because they have to really be interested in what you’re doing for that to happen.

We got that mid last year, and right now we’re applying to the Rare Disease Evidence Principles (RDEP) program, which is a new next-level addition to the orphan drug designation. This is the rare disease evidence principles program, and people are applying to it and getting accepted at the moment.

The caveat here is we kind of know what they’re aiming for at the high level, because they’ve said so. If you go look at the FDA website for the rare disease evidence principles program, you’ll see their blurb for it. This was announced late last year., but right now nobody really knows, including the FDA, how this program will pan out.

Realistically, for companies that go through it, in principle, it should speed the path to approval for these rare disease therapies where it’s somewhat more difficult to organize trials than for a more common condition. The theory is they’re going to rely more on preclinical evidence and more on post-approval assessment of the drug than on trials. But nobody really knows what that means in practice yet, but we’re engaging with the FDA on that topic right now, and we’ll see what they say.

There does seem to be somewhat of a shift happening in the FDA, but also in the UK. They announced starting next month, they’re going to be looking at accepting more computer modeling and are talking about 14-day Phase 1 clinical trials for certain approaches. I’m hearing Australia is being very proactive as well. I do wonder if all these fast-track schemes are making the UK or Australia a much more tempting place to set up and start trials. Could it catalyze the FDA to modernize and catch up?

There do seem to be signs in the FDA that it’s starting and maybe happening elsewhere in the US states, such as the Montana Right to Try exercise and Florida I believe are going in the same direction. I think what we’re looking at is that there is a pressure, right? It costs some stupendous, ridiculous amount of money to put a drug through the existing process. But, equally, one can spend a tenth of that and be treating patients in the Caribbean. You can’t have a world in which these two things exist without something changing.

I certainly think that the regulators feel the pressure of the existence of these other paths, because increasing numbers of companies are taking those other paths first before they come back to later to talk to the FDA. We’re going to see some new things, I can’t tell you about, coming up in the year ahead, on the lines of people doing things outside the system that are more sophisticated and definitely more of a challenge to the regulated system in terms of getting drugs into patients.

Something has to change, but the system will obviously react very slowly and probably only incrementally, but things have to shift, because ultimately, you’re looking at a world where the cost of a plane flight is much less than the savings you get by going to do a therapy somewhere outside the US. At some point, people will figure this out, and medical tourism jumps from being a small concern at the moment, a small and disorganized concern that’s only really used by very sick people, to something that is very widely used. Therapies for aging and therapies for common age-related conditions are probably going to be the catalyst for that, because now you have certainly a sizable increase in the number of patients who might consider doing this.

I think those pressures will obviously lead to change. Ultimately, it’s just a question of how fast. On a related note, with the recent green light given by the FDA for the Life Biosciences partial cellular reprogramming trial, it seems to suggest, whilst they’re still firmly on this one disease modification or organ at a time stance versus targeting the hallmarks of aging as an endpoint, they do seem to be open to rejuvenation-style therapies. Would you agree with that?

I think that the FDA is open to anything that treats a specific condition. They are certainly more open than they have been to gene therapies, but anything that’s new is going to get a lot of attention and probably needs a wealthy group behind it to push it through that level of attention and generate the sort of pressures behind the scenes to make the FDA conform to their desires, rather than vice versa. The situation hasn’t changed with regard to age-related diseases, you still can’t put a drug through the FDA for aging per se, TAME trial or no TAME trial, you still have to pick an indication and go for it.

What would you say is the biggest barrier to the FDA accepting biological age reduction, reversal, rejuvenation, or whatever people want to call it, of organs or tissues as a valid endpoint?

The FDA specifically wants you to improve function or feeling as a result of your therapy, and they will need to see the existence of a randomized controlled trial that demonstrates that your proposed endpoint, that is not function or feeling, connects to an endpoint that is function or feeling.

The reason why nobody can go run a trial on biological age is because you can’t point to a body of work that shows that biological age connects to in a way that the FDA is happy with. I mean, epidemiology, obviously, for these clocks, is everywhere, but the FDA will say, “Sure, that’s epidemiology. Now go run me a trial that shows, in a randomized, controlled way that this does match to some function that you care about for your indication of choice”.

This is exactly the problem that we have for the ability to regress atherosclerotic plaque. The FDA does not accept regression of atherosclerotic plaque as an acceptable pivotal endpoint for approval of a drug. Nobody can regress plaque, so nobody has conducted a randomized controlled trial to show that regression of plaque will do something good, where good is something that the FDA accepts meaning measures of function or feeling.

That’s your catch-22 whenever you’re doing something new in order to get your endpoint accepted, you have to have an awful lot of very expensive trials already conducted, which is one of the reasons why, for things like atherosclerosis, nobody really tries to do anything other than hit the surrogate endpoint of lowering LDL cholesterol, because to do anything else would require you to conduct an awful lot of work before you could even start to do a clinical trial.

We have a clever way around that. For the condition we’re pursuing, there is a functional endpoint we can pursue and improve, and therefore that’s one of the reasons why we picked the particular indication we picked, because that functional endpoint of exercise tolerance is very well established in the familial hypercholesterolemia population.

But back to the point everybody who comes in with some new endpoint that isn’t obviously function or feeling, the FDA will just say “no that’s not acceptable. Pick something else or go conduct a randomized controlled trial that demonstrates that your proposed endpoint connects to a functional endpoint and then come back and resubmit”.

Do you feel that if a few of these rejuvenation approaches do pan out and are successful? Let’s say, for instance, Life Biosciences announces next year that their Phase 1 results were positive and similar to what was seen in non-human primates and their mouse work. That means that they demonstrated that it does modify the disease. Obviously, they’re going to be recording things like epigenetic clocks. Do you think that that would strengthen the case with the FDA to accept these biomarkers as valid?

Because it’s the eye, it’s just a localized therapy and it won’t affect systemic biological age in the slightest, but everybody who does something that incrementally adds to things helps. All it takes is somebody, somewhere, doing a trial, and getting some data, and then at some point, it tips over into acceptance and biological age becomes a surrogate marker. But how long will it take to reach that tipping point? Who knows?

Certainly, there are very good arguments once you’re at the point of the FDA accepting epigenetic clocks as surrogate endpoints, but that’s a whole can of worms, because some of these clocks are clearly selective about what they what they react to, some clocks are going to react very differently to different therapies.

People are shopping for clocks to show off their preclinical data now, and they very much are just waiting until the FDA accepts clocks in a sort of fairly unlimited way. I do think it’s going to happen, I think they are probably very well aware of that, and they will be very reluctant to accept that first clock.

As supporting evidence, hopefully they’ll get more comfortable with that idea, and then that will pave the way for more rejuvenation-based approaches, or cellular resilience as Altos Labs describes it.

That was what the FDA is likely going to do, from an institutional perspective, considering its motivations, that’s separate and different from what should be done to accelerate the passage of therapies into the clinic. Certainly, I am one of those people who thinks that perhaps we should all be doing things in Prospera and building a separate ecosystem for early-stage clinical medicine, because the one we have kind of sucks.

For people who are not familiar with that, that’s a longevity hub in Honduras, and it ties in with the whole idea of a system outside the current system. Medical tourism is something that may put more pressure on regulators to get with the program and modernize. Back to REP-0004, what sort of timeline do you anticipate before you begin clinical trials?

If everything goes well with fundraising this year, because we have to raise a sizable amount of money to carry through the rest of our GMP manufacturing and run the trial itself in the best of scenarios, I think mid-2027 would be time for a trial start.

We’ll see how that goes. Because the market might be drifting back to sanity in the biotech side of the world, and the biotech market has been very disconnected from the broader market in terms of its tenor for some years now, but as the biotech market drifts back to being not terrible, then we’ll see if we can do that, otherwise there will be delays, and anybody who works in the field will tell you that biotech is basically an industry built on delay.

Although I think eventually, as a specific field of rejuvenation biotechnology, we see more of these therapies arriving, getting approved, and if we get some positive results, I do see that eventually our fairly unique sort of community will probably just merge with the greater whole in the end. It’ll all be part and parcel of it in the future, which is not necessarily a bad thing if it means that more people get access.

Everybody should get access to these technologies. It’s only really a matter of when rather than if at this point.

Yes, absolutely, it’s only a matter of when, but that’s a rather crucial matter if you’re 82, right? Weirdly, I think people have entirely the wrong idea about risk profile, and by people, I mean sort of this cultural feel and certainly the way that regulators behave. They look at very aged people and think “We can’t allow these people to take any risk whatsoever because they’re in terrible shape.”

Whereas, you know, if you’re old, what have you got to lose at this point, your personal tolerance for risk is probably completely different from what the regulators are going to impose on you as tolerance for risk. This is the eternal concern, one where the existence of a government and a regulatory system that removes choice from people, versus philosophies of government suggest more individual freedom is a good thing, and thereby, in medicine, people should absolutely have the freedom to go try things.

Of course, freedom comes with the responsibility that if you do something stupid, that’s on you, and I don’t think we live in an era in which that sort of viewpoint is looked upon favorably. We live in an era in which the prevailing consensus in government is that people should be protected from themselves, and that is why we ended up with a system that is the way it is.

So a lot of modernization is needed. Hopefully, these innovations in AI and drug discovery and their acceptance into clinical trial structures could hopefully speed things up. Of course, we’ve got this OSK clinical trial coming up, which potentially might help, but we’ll see.

Hopefully, we will see. I think the most interesting event for the OSK side of the house is going to be when some people start doing this using medical tourism. That is going to be interesting, because if you thought telomerase gene therapy was risky, then this is a whole new level of risky.

But somebody is going to try. There’s all sorts of cocktails of chemicals and gene therapies that have been tried in mice and the mice did relatively okay where they balanced the doses out and got it to work. Some people somewhere are going to try this, and maybe that ends up looking like the Wild West of early stem cell years and you have people turning up with cancers and maybe you don’t.

I don’t see it staying out of medical tourism forever. Certainly that it hasn’t shown up yet is indicative that maybe the medical tourism field has actually matured over the last 20 to 30 years to the point where they are starting to consider things more like an institution. But again, we’ll see.

Yes, we certainly will. Thanks for taking the time to speak with us today and updating us on your progress.