NEW PREPRINT: Scientists may have found direct evidence that aging is driven by the loss of cellular information, not just the accumulation of damage For decades we've focused on what aging cells accumulate. This paper focuses on what they lose: Information. Using a new technology called SeqTag, researchers measured gene expression, chromatin accessibility, and histone modifications in the same aging cells. What they found was striking: the regulatory systems that tell cells who they are become increasingly out of sync with age. The authors call this "molecular asynchrony." As cells age, chromatin structure, histone marks, and gene expression begin drifting apart. Regulatory entropy rises. Repressive chromatin erodes. Cells become less certain of their identity and more likely to drift toward alternative fates. This is what the Information Theory of Aging (ITOA) states: that aging occurs when cells lose epigenetic information, the instructions that tell the genome how to maintain youthful function. DNA may remain largely unchanged, but the system that reads it gradually loses fidelity. What's remarkable is that this paper doesn't just describe this phenomenon. It quantifies it. The authors measure increasing regulatory entropy, loss of H3K27me3-mediated repression, erosion of heterochromatin, weakening lineage fidelity, and increased cell-fate drift during aging. In progenitor cells, the barriers that normally preserve cellular identity become progressively weaker with age. Mechanistically, the study argues that aging is associated with increasing molecular asynchrony between chromatin accessibility, H3K27ac/H3K27me3 remodeling, and transcriptional state. This decoupling is accompanied by increased regulatory entropy, loss of repressive chromatin architecture, and weakening of lineage constraints. Genes affected are those involved in chromatin organization, DNA damage, and Wnt signaling, consistent with ITOA. Importantly, the authors provide quantitative evidence that age-related heterochromatin erosion lowers the energetic barriers that maintain cell identity, offering a potential mechanistic link between epigenetic information loss, cell-fate drift, and late-life disease susceptibility 👏

The largest-ever lifespan analysis of 601 mTOR modulators is now completed! This project has been driven by Rapamycin Longevity Lab (@omipalRLL) in partnership with @OraBiomedical (CEO @benblueAK, CSO Yan Ting Zhao, AI Engineer Ishan Ranasinghe, Co-founders @mkaeberlein , @BKennedy_aging, @mitchellblee33, @jangruber467 & Jason Pitt). Our mission has been to identify compounds even more potent than Rapamycin in extending lifespan in roundworms. I am deeply grateful for the community’s support for this historic project and big thanks to all our sponsors who made this possible! Our Gold Sponsors: ✅ Melissa Burdick & Brian Burdick: Great tech leaders and e-commerce pioneers. Connect with Brian and Melissa on LinkedIn to follow their work. ✅ Antoine Dusséaux: A London-based entrepreneur. Connect with him on X via @adssx ✅ Dmitry Sadovnikov: Connect with him on LinkedIn or X via @ksajxai ✅ Ciarán Murray: A longevity enthusiast and tech founder of @OlasProtocol. Connect with him on X via @C1aranMurray ✅ Anonymous: Two anonymous contributions to the project and one by Anonymouse. Other Sponsors of the Project: ✅ @agelessrx_ : A cutting-edge telemedicine platform specializing in making various longevity interventions accessible, actively involved in research and clinical trials. ✅ Winslow Strong: Dedicated to advancing human health and wellbeing. Follow him on X @winslow_strong. ✅ Dr. Grant Fraser: Specializes in longevity medicine, integrating lifestyle interventions with personalized medical treatments. ✅ @OpenCuresOrg: A unique online platform empowering individuals, health professionals, labs, and researchers to accelerate longevity interventions. ✅ Revi Health (@johanhedevag): Modern clinic in Sweden combining regenerative medicine, performance health, and longevity protocols for measurable results. ✅ @healthspanmed: The first-ever digital medical clinic helping patients fight cellular senescence and regain control over the levers of aging. ✅ Rapamycin Longevity Lab (@omipalRLL): Our mission is to become the leading expert around mTOR inhibitor-based combinational therapies for longevity. ✅ People in the longevity community: Thank you for every donation, like, and share. Your support has fueled this project! PS 1: Big thanks also to Victor Björk for the help with the fundraising! PS 2: All lifespan data is now available on the Rapamycin Longevity Lab’s LID database (link in the comment section). You can find the top 20 and bottom 20 lists right here in the social media image! Big thanks to Andrew Steele (@statto) for the great suggestion to create a bottom list as well! PS 3: The next step is to collaborate with different parties to analyze the data and also see if the data translates to other species. Reach out if you want to collaborate!

And it's true worldwide, of course. Something must be done.

The wait is almost over. Next week the complete dataset from the largest mTOR modulator screening project will go live in the Longevity Intervention Database (LID). In partnership with @OraBiomedical and our great sponsors we have completed a rapid lifespan analysis of 601 mTOR modulators in roundworms. Our goal in open-sourcing this foundational data is to allow AI, labs, researchers and companies to accelerate progress and move the longevity field forward. Many more screening projects will be launched by the Rapamycin Longevity Lab (@omipalRLL) in collaboration with Ora Biomedical and others. But today I wanted to give you a sneak peek at the updated leaderboard. Here are my three key takeaways from this new phase of data: 1⃣ We have more than doubled the number of compounds beating Rapamycin. In our first phase, we identified 5 compounds that outperformed the best recorded Rapamycin baseline (27% median lifespan extension). With this second release we now have 11 compounds sitting above the red line. 2⃣ 24 new compounds qualified for the top list. It is fantastic to see these new entries. It will be incredibly interesting to dig deeper into the data to understand how they target the mTOR pathway in different ways. More to come on this. So stay tuned! 3⃣ Omipalisib continues to be a standout compound. The Rapamycin Longevity Lab was the first to discover its lifespan-extending properties in worms. We have conducted and are currently conducting experiments across multiple species to see if we can translate these results beyond worms. We are also evaluating combination therapies to see if we can enhance the longevity effects even further. If you are a researcher or organization interested in collaborating either to support upcoming screening projects or to validate any of these top-performing compounds in other strains then please reach out. Let’s collaborate and move the field forward together! And big thanks to all who have helped out with all the work so far!

The first case of a SENS spinout getting this far! Massive congrats to Oki and his team.

Can someone point me to a serious longevity science discussion where lifespan is promoted to the exclusion of healthspan? There’s loads of evidence outside supercentenarians too—diet, exercise, etc in humans, and most interventions in animals like rapamycin in mice extend both.

I think this is a straw man, Eric! Very happy to discuss on your podcast. :) x.com/statto/status/20537315…

It’s time for an update of the Rapamycin Phenotype Responder Matrix. Two weeks ago @BradStanfieldMD published the result from his clinical trial around Rapamycin (pubmed 41985884). The aim was to see if Rapamycin in older adults in combination with exercise could increase its effects. The reason why this is interesting to test is because mTOR activation tends to increase by age and this may result in less muscle gains. The results from the study point towards that Rapamycin is most likely not a physical performance enhancer. This is not something unique to just rapamycin. The same thing can apply to other interventions such as fasting, calorie restriction, protein restriction, metformin, aspirin, GLP-1 agonists, NAC, antioxidants, cold showers etc. Possible reasons why these interventions blunt the effects of exercise are 1) Too big inhibition of anabolic processes, 2) Too big neutralizing effect on acute muscle stress when it comes to building new muscle, 3) Too little energy to be able to challenge the muscles in an efficient way and/or 4) Insufficient amino acids and calories to build muscle. I would argue that many of the “longevity” interventions out there touch on one or several of these reasons. It’s a trade-off dependent on dosing protocol and highlights the importance of a personalized approach aligned with personal goals and pre-conditions. The reason why I created the Phenotype Responder Matrix last year was to structure and combine both clinical trial data and self experimentation N=1 data in one view around a specific longevity intervention. The pilot intervention for this matrix is Rapamycin and the long term goal is to build this type of matrix for many different longevity interventions. If you have suggestions for improvements or any other feedback just reach out. All feedback is welcome, even the tough ones. What I really like with this phenotype responder matrix is that if a group or individual does not get an effect or gets a negative effect it does not mean the intervention will not work for others. The matrix points towards the fact that personalized longevity medicine is the right way forward. There is no one shoe that fits all. Things are often more nuanced than just black and white.

To reverse aging we will need to fully comprehend this. It is a massive challenge worth taking on.

A new lifespan study in mice was published this month regarding a combination therapy where Urolithin A, Quercetin, NR, Alpha-lipoic acid and SRN-820 were combined. It showed a 33% increase in median lifespan. They also tested Rapamycin alone and it showed a 21% increase. While these aren't any big values they point once again toward that combination therapies are the way forward. Very few resources are currently put into researching combinations and my guess is that when we start to see really big lifespan effects then it will become much easier to forecast whether an intervention really works in humans through various metrics in much early stages. One very interesting thing regarding the study would have been to explore each intervention individually because I believe there is potential to improve the cocktail recipe. Perhaps some compounds could be removed due to having little to no effect and others could be added. But step by step we are moving ahead! I have also added the four data points from this study to Rapamycin Longevity Lab's (@omipallRLL) Longevity Intervention Database (LID). So now we have more than 2800 data points there!

Last week Dr. @BradStanfieldMD the results from his Rapamycin Exercise clinical trial and they showed that Rapamycin is not a physical performance enhancer. To some this felt like a "failure". To me, this highlights the essential interplay between anabolic (building up) and catabolic (cleaning and breaking down) processes. Most “longevity” interventions such as calorie restriction, fasting, Rapamycin etc activate catabolic processes. To optimize physical performance then activation of anabolic processes is needed to a certain level. We can’t floor the gas (anabolism) and the brake (catabolism) at the same time and expect a world-record in physical performance. Different interplays between anabolic and catabolic processes serve different life goals and biological states, each with its own benefits and trade-offs. I’ve been sketching on a X model around this to try to make things a bit clear. So here are some potential goals to optimize for. 1️⃣ Reproduction: Optimizing for reproduction and fertility but the trade-off is not optimal performance or lifespan. 2️⃣ Performance: The elite athlete who tries to push the limits. The trade-off is not optimal reproduction or lifespan. 3️⃣ Survival: Optimizing for a longer life. The trade-off is not optimal reproduction or performance. 4️⃣ The Middle Way: The trade-off is that nothing is optimal but not bad either. 5️⃣ & 6️⃣ Radical Life Extension: Aiming for a radically long life. We don’t yet know if it's possible or what benefits or trade-offs will be. The value of this model is clarity. If you want Performance (2), Rapamycin might get in your way. If you want Survival (3), Rapamycin is a logical ally. Personally, I am targeting Radical Life Extension (5). Since we don't have a proven roadmap for State 5 I try therefore to align my current lifestyle with Survival (3) as a potential bridge to the future. Only time will tell if this is the correct path forward for me. So before we pick up our next “longevity” intervention I think it’s good to ask ourselves: Which longevity state is this intervention aligned with and is that what I’m really aiming for? PS. Please keep in mind that this is an unvalidated and early-stage model. All feedback is welcome as always! Even the really tough one.

We have added over 170 new data points to the Longevity Intervention Database (LID). This database is developed by the Rapamycin Longevity Lab (@omipalRLL) and it’s a public-access resource and the goal is to soon start to generate massive amounts of data to it. The purpose with this is to empower AI, companies, labs, researchers and other people to accelerate the research so that we move closer to a world without age-related diseases. Most of the new data points that have been added are focused on the IIS pathway, which alongside the mTOR pathway is a primary focus of our lab. This dual interest also led to our discovery of Omipalisib (GSK2126458) which showed very promising lifespan data in roundworms. We are now working to translate these findings to other species such as flies and mice. We have three months of data for our mouse study but because of a lack of funding we may need to cancel the experiment this month. If anyone is interested in helping with $10k in funding the study then we could at least obtain important data on median lifespan and health metrics (such as grip strength, activity, body weight and body temperature) for Omipalisib. Reach out if you want to help and if you cannot help out financially please help by spreading the word!

Our core mission at Rapamycin Longevity Lab (@omipalRLL) is to take mTOR inhibitors to the next level by developing combinational therapies. We are particularly interested in exploring the life-extending effects of combining mTOR inhibition with glucose regulation. To accelerate this research we are proud to announce a new partnership with Metformin Ventures (@longevityVentur) on @pumpdotscience! This collaboration brings us together with @LinusPeters, the visionary founder of Metformin Ventures and the Swedish Longevity Cluster. Linus has long been a driving force in the longevity community, organizing different events dedicated to the goal of solving aging. With our missions perfectly aligned we are ready to push the boundaries of human longevity together. We’re kicking things off with a livestream this Friday. So come and meet Linus and see how we’re planning to move the needle on aging.

Excellent article outlining the longevity benefits of Rapamycin cureus.com/articles/439007-t…

There’s an argument that GLP-1s are playing a critical role in society, not just for weight loss, but as a technology of imagination. Something humans are in desperate need of as we try to reconcile with AI becoming the new fabric of society. GLP-1s expand human imagination by breaking psychological ceilings. Important because AI expands human capability without necessarily expanding self belief. The future requires us to imagine new versions of ourselves and GLP-1s show humans how a simple injection remaps what they can aspire to become. Most people live with a fixed self-model. Something like “I’m addicted,” “I’m obese,” “I can’t change” or "I can't do that." Their mind struggles to simulate a different version of themselves, especially after countless failed attempts to change. When someone takes a GLP-1 and their cravings collapse overnight, or they overcome some other addiction, their imaginative horizon expands. They now see a future self that previously felt impossible. This is helpful as AI plays a dual role: today it empowers you; tomorrow it replaces you. Making it simultaneously thrilling and threatening. Humans need a psychological boost, a power up, to help us unshackle our self concepts. Of what we can become individually and as a species. So that we can reconcile with the idea that if AI does all that we do today, it’s ok, we can evolve. GLP-1s demonstrate that neuropsychological locks and limitations can be removed. They show that the cognitive barrier to seeing a new version of oneself can be knocked down in a single injection. If it’s a GLP-1 for weight loss and addiction today, can we imagine a GLP-1 equivalent for reversing age, sleep, fitness, creativity, energy, mood, want for life, etc. The burden is on why we should limit our imaginations right now.

When ppl want something they can't have, they create moral frameworks for why they never really wanted it anyways (i.e. body positivity). There will be GLP-1 equivalents for anti-aging. Humanity will then clamor for Don't Die and delete remembrance that we ever defended death.