Rejuvenating Muscles in Mice With Senomorphic Treatment

Date Posted: July 30, 2025

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Rejuvenating Muscles in Mice With Senomorphic Treatment

A recent study investigated senescence in mouse and human skeletal muscle tissue. The authors demonstrated that the antiviral drug maraviroc reduces senescence and improves muscle health in aged mice [1].

Aging muscle tissue

Senescent cells are one of the hallmarks of aging. One of their key characteristics is the presence of the senescence-associated secretory phenotype (SASP), which includes many pro-inflammatory compounds.

These researchers focused specifically on senescence in skeletal muscles, pointing to previous studies showing conflicting results regarding senescence in muscle function. On one hand, one study showed that treatment with the senolytic drugs dasatinib and quercetin, which selectively kill senescent cells, increased muscle strength and function in aged mice [2]; on the other, a different study suggests that muscle regeneration can be achieved with pro-senescent therapy [3].

Due to such conflicting results and the field’s insufficient understanding in this area, these researchers aimed to build an atlas of senescent cells in skeletal muscle. They believed that this could aid in finding better treatments for sarcopenia, an aging-related disease characterised by a decrease in muscle strength and functioning.

Senescence in muscles

The researcher used biopsies from the hamstring muscles of 10 male donors: five young (19-27 years old) and five aged (60-77 years old), and they measured the gene activity in cells isolated from those biopsies. In their analysis, they only used mononucleated cells prone to senescence and removed the differentiated, post-mitotic myofibers.

Analysis of epigenetics and gene expression divided the cells into 12 clusters of muscle-resident cells. The aged and young cells differed regarding the numbers of cells in clusters, with aged cells showing lower numbers of muscle stem cells among other cell types.

Next, they integrated information from four senescent gene sets (SenMayo, CellAge, GenAge, and Senescence Eigengen) to assess these cells’ senescence score. This score, along with multiple markers of senescence and inflammation, demonstrated increased senescent cell prevalence in four cell types in aged muscle compared to young muscle.

Deeper analysis of SASP dynamics in aging muscle cells identified a subset of SASP factors whose expression was shared among four cell types; however, over 30% of the SASP was cell type-specific. The SASP also impacted many communication pathways in aged muscles, and SASP-mediated interactions were stronger in aged cells than young ones.

Rejuvenating muscles

One of the key components of the SASP, the CCR5 receptor, and the CCL3, CCL4, and CCL5 chemokines that bind to this receptor were significantly elevated in aged muscle stem cells and whole muscles compared to young ones.

This was an important observation as the same group, in a recent study [4], used the CCR5 agonist maraviroc (MVC), an antiviral drug used to treat HIV infection, to reduce inflammation in dystrophic mouse muscles. This prompted them to test maraviroc’s potential senomorphic properties in muscle aging.

First, the researchers tested a high-dose short-term (HDST) treatment regimen, treating 18-month-old mice for 3 months with high doses of maraviroc. This treatment led to rejuvenated and healthier muscles. The researchers observed that maraviroc treatment increased muscle mass and fiber size, reduced inflammation, and improved muscle function, such as increased grip strength, higher running speed, and longer running distance. On the molecular level, the researchers observed an increase in the number of muscle stem cells and a decrease in pro-inflammatory macrophages, decreased levels of cellular senescence, reduced expression of SASP-related genes, and decreased SASP-mediated cellular interaction, all suggesting that maraviroc has senomorphic potential in the treatment of sarcopenia.

Such observations were made only when this regime was applied to aged (18-month-old) but not young (2-month-old) mice, suggesting that maraviroc has aging-specific effects.

Different doses and timing were also tested in aged mice, with low-dose, long-term treatment (6 months) showing positive results, but this was not the case for low-dose, short-term treatment.

Regulating senescence and the SASP

Furthermore, the researchers aimed to understand which transcription factors govern senescence and SASP induction in the muscles of aged humans. They identified many transcription factors (TF), including the known players in senescence and SASP regulation, such as NF-κB1 and C/EBPB. However, they focused on the less-explored transcription factors that belong to the AP-1 family: ATF3 and JUNB.

Through employing many molecular biology techniques, they concluded that ATF3 plays a role in regulating the expression of many genes with senescence-related functions. Their results suggested that genes activated by ATF3 are elevated and genes repressed by ATF3 are downregulated in senescent cells; however, there were differences in the specific upregulated or downregulated genes that depended on cell type.

The second transcription factor, JUNB, did not affect the expression of senescence markers but played a role in SASP. The researchers suggest JUNB can be a “key upstream TF inducer of SASP production.” JUNB expression was increased in aged muscle stem cells derived from mice and human samples, and 54 human SASPs that were regulated by JUNB were also highly expressed in aged mouse muscle stem cells, suggesting a conserved role of JUNB in mice and humans.

Due to the human and mouse similarities, the researchers utilized a mouse model for their subsequent experiments. The expression of the previously mentioned SASP genes was lower in the muscle stem cells isolated from mice with inactivated JUNB, compared to the control. On the other hand, when the researchers overexpressed JUNB in the muscle stem cells of the young mice, the expression of some SASP genes was increased.

Potential therapeutic candidates

This study created the first atlas of senescence in human skeletal muscle. The authors hold that it can help the field better understand the heterogeneous nature of senescence and thus improve the design of relevant therapeutics.

While this study identified maraviroc as a potential good candidate for sarcopenia, there is still a need to test it in humans. The authors also suggest that future studies should “conduct a focused screen for senolytic or senomorphic compounds that target the unique features of senescent cells in skeletal muscle” to identify other potential candidates to treat sarcopenia.

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Literature

[1] Li, Y., Li, C., Zhou, Q., Liu, X., Qiao, Y., Xie, T., Sun, H., Ong, M. T., & Wang, H. (2025). Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia. Nature communications, 16(1), 6207.

[2] Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., Onken, J. L., Johnson, K. O., Verzosa, G. C., Langhi, L. G. P., Weigl, M., Giorgadze, N., LeBrasseur, N. K., Miller, J. D., Jurk, D., Singh, R. J., … Kirkland, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. Nature medicine, 24(8), 1246–1256.

[3] Saito, Y., & Chikenji, T. S. (2021). Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics. Frontiers in pharmacology, 12, 739510.

[4] Li, Y., Li, C., Sun, Q., Liu, X., Chen, F., Cheung, Y., Zhao, Y., Xie, T., Chazaud, B., Sun, H., & Wang, H. (2025). Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis. Nature communications, 16(1), 1324.

Date Posted: July 29, 2025

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The Tale of One Tower: SF-Based Vertical Longevity Village

In downtown San Francisco, an entire tower is becoming a hub for longevity, AI, crypto, and robotics. It just hosted its first longevity conference.

How does a group conquer a big city?

The longevity community unites tens of thousands of researchers, founders, and enthusiasts, but this is mostly done virtually. Things began to change after Zuzalu, a first-of-its-kind “pop-up city” (rather village), which existed in Montenegro for two months in 2023. Funded largely by the multi-millionaire founder of Ethereum, Vitalik Buterin, it was a gathering of several hundred eager, mostly young people with somewhat overlapping interests, including crypto, AI, and longevity.

Zuzalu was inspired in part by the ideas of Balaji Srinivasan, former CTO of Coinbase. Balaji, as he is referred to in these circles, coined the term “network state”: a new type of community designed to bring like-minded people together, both virtually and physically. The term refers to a sprawling concept that outlines several principles, such as having a unifying idea, but it hardly prescribes any particular realization. Theoretically, network states can have either a lot of, some, or no physical presence.

After Zuzalu, many alumni immediately set off to improve the formula. Some recreated it rather faithfully with minor tweaks. Others eyed “taking over” Rhode Island using political action. Vitalia, a two-month-long longevity-oriented event on the tropical island of Roatan, was a notable step forward for two reasons. First, it was based on (and in) the free economic zone of Prospera, which has loose regulations that proved to be a great fit for biotech startups, enabling them to start selling their therapies after a successful Phase 1 trial. Second, a small permanent community was established after the several-hundred-strong “pop-up city” phase ended.

While places like Prospera, which creatively juggle regulations and are somewhat of a state within a state, are attractive, they can only be found (for now) in countries far away from the centers of science and innovation. Getting closer to those centers means hitting barriers like a high cost of living.

Then, two things happened in rapid succession. From March to May, the Vitalism movement held Vitalist Bay, a pop-up village in Berkely, California, featuring a series of weekly longevity-related conferences. Just as Vitalist Bay ended, and its residents dispersed, another project nearby kicked off, and it was even weirder – in a good way.

It takes a vertical village

In March, three young German entrepreneurs, Jakob Drzazga, Christian Nagel, and Christian Peters, bought a 16-story tower in the Mid-Market area of San Francisco’s downtown, one of the city’s infamous hotspots of homelessness and the ongoing fentanyl crisis. Real estate prices in the neighborhood have seen giant swings in recent years: the three buyers shelled out 11 million dollars, which is roughly double the building’s previous selling price from 2023 but much lower than the $62 million tag it carried less than ten years ago. Still, Jakob and the two Christians had to borrow heavily, basically betting their future on the project.

Their idea is to transform the tower into the ultimate co-working and co-ideation space for people engaged in several cutting-edge areas, such as crypto, AI, robotics, and longevity. As of now, the tower technically does not offer co-living, but some kind of an arrangement will probably be reached.

Each floor has a purpose. There’s a robotics lab, a biochemistry lab, a gym, a relaxation space, and so on. 11th is the longevity floor, run by no other than Laurence Ion, longevity investor and entrepreneur, co-creator of VitaDAO, and an organizer of both Zuzalu and Vitalia.

Laurence’s overarching goal is to build a real, physical longevity city. There’s a name – Viva City – but not much more. However, you can already get early membership. Laurence also offers $1 million for facilitating a fateful contact with the leadership of a state that chooses to lend a piece of its territory for this project.

Meanwhile, Laurence used the tower for a slightly less ambitious project: a ‘vertical pop-up village’ called Viva Frontier Tower, centered around longevity, AI, and crypto, and touted on its website as “the healthiest, most productive 6 weeks of your life.” In a tried and tested fashion, every section is built around a conference (it seems like all conferences are now called “summits”), which can hopefully attract top-tier speakers and enough paying audience to not bankrupt the organizers.

I was invited and flew in from Seattle the day before. Judging by the map, the location was amazing: in the heart of the downtown, just a couple of blocks away from a BART station. I love trains, but in this case, considering the late time and what I knew about the destination, I grudgingly took an Uber. When I walked out of the hotel next morning, I realized I’d made a wise decision.

Mid-Market might be slowly getting better, but it’s still very much unwell, full of gut-wrenching scenes of miserable, broken, ill people let down by the society they live in. However, the crisis made the real estate cheap, which made buying the tower possible, which might, with time, help steer the area towards better fortunes.

Laurence confirmed to me that this is the idea: “The neighbors can be… interesting. It’s not the most pleasant first impression for some people, but I don’t think it’s dangerous. They are mostly harmless people on drugs. We are revitalizing the area. After COVID, many businesses closed, and the area became empty. We are reclaiming the empty spaces for the community.”

The summit on the 11th floor

The conference started with a rooftop rave and continued with a quirky mix of talks ranging from hard science to wellness to politics to topics that would have been deemed completely outlandish until very recently. Laurence kicked off the action by presenting the conference and talking about VitaDAO, probably the most successful decentralized science project in the longevity space.

On the science-heavy side, we had people like Amit Sharma, a senior researcher at the Lifespan Research Institute (formed by the merger of SENS Research Foundation and Lifespan.io). Amit presented his lab’s cool research into cellular senescence, which we have covered extensively. The list of big names in longevity who had chosen to appear, lending a lot of credibility to the new conference, also included Aubrey de Grey, Greg Fahy, Marco Quarta, Irina Conboy, Matthew O’Connor, and others.

Aubrey, known for his ability to always read the room, chose to present without slides, forgoing the scientific stuff, such as his foundation’s Robust Mouse Rejuvenation project. Instead, he gave a fast-paced, passionate talk centered on how to promote the longevity cause and aptly named “How can we make aging the new COVID?” In particular, he weighed in on the raging debate on whether the longevity field should be wary of overpromising and underdelivering when trying to recruit public support.

According to Aubrey, developing working interventions first and presenting them to the public as the basis for asking for support and money “is not the only way forward.” Cancer research, he said, boomed after the “War on Cancer” was declared more than half a century ago, even though oncologists had little idea of how to actually tackle the disease. They wildly overpromised and underdelivered, yet this seemed to only reinforce society’s resolve to find the cure. For decades, immense funds poured in, and today, we have finally made some real progress. Why should the war against aging be any different? If anything, we now have more understanding of aging than we had of cancer 50 years ago and more working interventions, at least in preclinical models.

A notable appearance was made by Ryan Field from Kernel, Bryan Johnson’s company that has been quietly working for several years on measuring the brain. Ryan presented not just his company’s vision, but the finished product: a neat-looking fabric-clad grey-and-black helmet that Kernel has started to market to clinics and research institutions. The helmet “generates detailed maps of activity in the brain that provide a deep and scalable understanding of disease state and treatment response.” In particular, Ryan touted functional measurements of mild clinical impairment (MCI) and depression. The tech uses light to measure oxygen in brain tissue, Ryan said.

Ryan Field from Kernel holding the helmet, which is part of the company’s Flow2 platform

Impressive as the helmet was, it couldn’t match the audacity of not one but two companies present at the conference that are actually working on mind uploading: creating a computer-based copy of the human brain that is faithful enough to serve as your ‘electronic double.’ Mind uploading has been thought to belong entirely to science fiction for the foreseeable future, but, apparently, there are actual companies with actual funding who think that this mind-blowing goal is already within our reach.

Both Jessica Radley from Nectome and Michael Andregg from Eon Systems mentioned one of the most impressive scientific feats of the last decade: completing the connectome (full map of the neuronal connections) of a Drosophila fly’s brain, now available online. Both companies are building on it to create the connectome of a human brain, while Nectome also looks towards preserving the genome, transcriptome, epigenome, and, basically, “every biological macromolecule” in the brain to faithfully reproduce a human’s personality. Today, the cost of the compute is still prohibitively high, but Jessica and Michael hope that Moore’s law will continue to hold true.

Michael made a suspiciously rosy prediction: the connectome of a mouse brain will be completed as soon as the next year, and a human one will be done over the next few years. However, there’s a major catch: with Eon System’s tech, it’s a one-way ticket to virtual existence. To map the connections, the brain must be artificially enlarged and sliced; this is how the fly’s brain was analyzed, using microscopes. There’s no way back to the physical world from there: in the best-case scenario, “you” will end up in a virtual reality built by Eon. Michael promised that it will be fun.

Jessica Radley from Nectome presenting. Behold a fly’s brain!

Like several other recent conferences, this one veered quite a bit towards politics and public policy. If you think mind uploading is a long shot, so are the political ambitions of Zoltan Istvan, a transhumanistic author and politician who gained some notoriety running for presidency in 2016 for the Transhumanist Party. In 2018, he ran for Governor of California for the Libertarian party; in 2020, he challenged Trump in the Republican Party’s presidential primaries; and, finally, earlier this year, Zoltan announced another run for California governorship, this time as a Democrat. So, he has been a member of four parties in total in seven years. Zoltan is also quite outspoken about extreme longevity, having starred in the documentary Immortality or Bust.

From the conference’s pulpit, Zoltan outlined his program, which actually made a lot of sense to me. Zoltan is one of the handful of political figures who understand the enormity of the impact that AI is going to have on our society in a matter of years and the need to protect people from the resulting massive job loss, building an economy of AI-based abundance. Education, healthcare, and the social safety net will all have to be heavily modified for this new era, which will also rush in new possibilities for fighting aging. Unfortunately, nation-wide, Zoltan’s warnings and ideas will probably fall on deaf ears, and mainstream politicians will continue to play catch-up with the reality of the AI revolution.

One tower fits all

During one of the breaks, I joined a tour of the tower led by Laurence. The building’s age is showing, but it’s holding fairly well. WeWork used to be one of the residents, and several floors still have an entire co-working infrastructure in place: offices, chairs, tables, beanbags, conference rooms. This already promises a nice return on your $190 monthly fee if you live in the area and are looking for a coworking arrangement. The membership also gives you access to the gym. Here’s where the tower’s uniqueness kicks in: pay a bit extra, and you’ll have access to the wet lab! If this is still too steep, there are scholarships.

The tower’s plan. Fancy visiting the Spaceship?

“It’s the first permanent space for the longevity biotech community where people can co-work, hold events, exercise, and have healthy food together,” Laurence said. “We’re progressively adding more facilities, like a biohacking clinic, a nootropics bar, biological age testing, blood storage, IV therapy, a DEXA scanner, and hyperbaric oxygen therapy. We’ve pivoted slightly to focus on all frontier tech communities, not just longevity. This brings in much more energy. There are many people in crypto and AI who want to live longer; they might not come specifically for a longevity floor, but they come here for the broader community and end up engaging with and helping the longevity field.”

Like probably every second building in San Francisco, the tower hosts a startup incubator program. How does it work? “We hold sessions with mentors who help companies prepare for a demo day where they can present to investors and hopefully raise money,” Laurence said. “The vast majority of the companies currently in the program are longevity biotech companies.”

However, the tower is also half-empty, scrappy, with signs of ongoing construction. It looks like a work in progress and like it would take a serious effort to fulfill its undeniable promise. Laurence, however, is optimistic: “It’s going well, though it’s not in the bag yet. There’s a lot of buzz, and people in the city and the tower love it, so it feels like a success. The tower is buzzing, at least during the pop-up city events. I hope this feeling will continue as people get used to the space and feel like it’s a true community home, not just a coworking space you visit once a week. People are really connecting here. We’re already talking about expansion, perhaps to a hotel nearby.”

The longevity floor sports a quirky semi-industrial design.

Ich bin ein Berliner

The founders’ origin is not the only reason the startup behind the Frontier Tower is called BerlinHouse. They apparently drew inspiration from the reunification of the German capital in the late 20th century.

“After the fall of the Berlin Wall, tens of thousands of people left East Berlin, leaving hundreds of buildings unoccupied,” the tower’s website says. “This vacancy gave rise to vibrant communities that created clubs, art spaces, collectives, and hacker houses which make Berlin so special. Today, a similar opportunity is emerging in downtowns worldwide, where empty office spaces are becoming the new frontier. Now is our chance to reclaim these spaces, redefine urban living, and foster deeper connections in our cities.”

They have a point. Opportunities are indeed emerging. Despite the attempts by many big companies to bring their workers back to office, the centrifugal force of remote work is probably already unstoppable, and the advance of AI is poised to accelerate this process even more. As towers in the world’s cities get emptied, they might become the pillars of future network states.

Jakob Drzazga, CEO of BerlinHouse, said that the project was “an opportunity to fundamentally rethink how we use buildings,” and that much of the inspiration came directly from earlier pop-up city experiments like Zuzalu. It’s not just about space usage.

Co-habitation Zuzalu-style allows people to enjoy the best of both worlds: collaboration at almost the speed of online tools like Zoom with all the benefits of live, offline communication. I’ve experienced first-hand how talking to other people and even watching them work can snap people out of procrastination or writer’s block.

Even though his hands are full with the Frontier tower, Laurence continues to pursue the much more ambitious vision of Viva City. “Viva City is a bigger project, and we are growing as a community while talking to governments about potential locations,” he said. “To grow the community, we are building a ‘one-stop shop’ product for longevity and seeding these towers in major cities as hubs for the Viva City community and our extended family.”

Apparently, you don’t have to choose between a faraway destination and a bustling downtown. You need them both. “You still need those special jurisdictions for regulatory freedom,” Laurence admitted. “But it’s also important to have hubs in every major city where people can get a taste of the community. They can come into a local space, learn about the vision, and realize that if they truly want to innovate, they need to go to the new frontier – that crazy island in the middle of nowhere.”

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Date Posted: July 28, 2025

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Fighting Osteoarthritis by Targeting Fatty Acids

In the Cell journal iScience, researchers have published their discovery of a protein that inhibits osteoarthritis in mice by diminishing fatty acid production.

Fats in the wrong place

Previous work has found a strong link between obesity and osteoarthritis of the knee [1]. While the increased weight itself may be a factor, fatty acids themselves are linked to arthritis in the knee [2]. Excessive amounts of a related compound, acetyl-CoA, have been found to be harmful in this context, and the enzyme ACOT12 breaks apart acetyl-CoA, leading to better outcomes in a mouse model [3]. Other components of fatty acid metabolism have also been linked to osteoarthritis progression [4].

Sterol regulatory element-binding transcription factor1 (SREBP1) is a key factor in the generation of these fatty acids, and the researchers note that its expression is linked to disc degeneration. They also point to research showing that the mouse gene Sesn2 inhibits the production of these fatty acids; mice without this gene swiftly accumulate deadly fat deposits in their livers [5]. As indirect upregulation of this gene has been associated with better knee cartilage and healthier cartilage-generating chondrocytes [6], and its overexpression ameliorates spinal arthritis in rats [7]. Therefore, these researchers sought to determine the link between SESN2, fatty acid synthesis, and outcomes in knee osteoarthritis.

SESN2 is broadly beneficial against arthritis in mice

The researchers’ first experiment involved human donor cartilage divided between healthy and damaged samples. As expected, the damaged samples had less SESN2 than the healthy samples, along with more expression of destructive factors and less expression of constructive ones; less SESN2 was found to be directly correlated to more lipid deposits and more of the metalloproteinase MMP3, which degrades cartilage. Other testing found that there was also less SESN2 in osteoarthritic model mice than healthy ones, and older wild-type mice were found to have less SESN2 than younger ones.

A follow-up experiment involved using RNA to directly silence Sesn2 in murine chondrocytes, and the results were similar to the damaged human samples, with increases in metalloproteinases and more destructive factors along with a corresponding decrease in constructive ones. Crucial genes, including sirtuins, were downregulated by this silencing as well. These Sesn2-silenced chondrocytes also had significantly increased lipid accumulation along with increased markers of cellular senescence, including p16, p21, and p53.

On the other hand, upregulating Sesn2 improved the balance between destruction and construction in chondrocytes stimulated with the inflammatory factor IL-1β. Lipid accumulation in the affected cells was significantly diminished, and senescence biomarkers were reduced.

Establishing the link

These results were found to indeed be due to SREBP1, which the researchers confirmed to be inversely correlated with Sesn2 expression. Directly activating this factor through ammonium chloride resulted in very similar effects as downregulating Sesn2, increasing metalloproteinases along with the enzymes that produce fatty acids. A mouse experiment demonstrated this relationship; mice that had upregulated Sesn2 but also had SREBP1 forcibly increased suffered from the same problems as mice that had downregulated Sesn2.

However, upregulating Sesn2 without directly affecting SREBP1 led to across-the-board benefits against osteoarthritis in wild-type mice that had experienced a debilitating knee surgery. The affected mice had less signs of knee osteoarthritis, significant decreases in fatty acids, reductions in swelling, reduced oversensitivity to pain, and more endurance.

The researchers believe that targeting SESN2, therefore, is a valid and viable potential therapy for treating osteoarthritis in people. However, this study did not involve drug discovery, and a mechanism for accurately targeting SESN2 or SREBP1 has not yet been determined. Substantial further work must be done in order to determine how this approach could potentially be used in the clinic.

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Literature

[1] Reyes, C., Leyland, K. M., Peat, G., Cooper, C., Arden, N. K., & Prieto‐Alhambra, D. (2016). Association between overweight and obesity and risk of clinically diagnosed knee, hip, and hand osteoarthritis: a population‐based cohort study. Arthritis & Rheumatology, 68(8), 1869-1875.

[2] Wu, C. L., Jain, D., McNeill, J. N., Little, D., Anderson, J. A., Huebner, J. L., … & Guilak, F. (2015). Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury. Annals of the rheumatic diseases, 74(11), 2076-2083.

[3] Park, S., Baek, I. J., Ryu, J. H., Chun, C. H., & Jin, E. J. (2022). PPARα− ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis. Nature communications, 13(1), 3.

[4] Jeon, Y. G., Kim, Y. Y., Lee, G., & Kim, J. B. (2023). Physiological and pathological roles of lipogenesis. Nature Metabolism, 5(5), 735-759.

[5] Fang, Z., Kim, H. G., Huang, M., Chowdhury, K., Li, M. O., Liangpunsakul, S., & Dong, X. C. (2021). Sestrin proteins protect against lipotoxicity-induced oxidative stress in the liver via suppression of C-Jun N-terminal kinases. Cellular and Molecular Gastroenterology and Hepatology, 12(3), 921-942.

[6] Wu, Y., Li, X., Meng, H., Wang, Y., Sheng, P., Dong, Y., … & Wang, X. (2024). Dietary fiber may benefit chondrocyte activity maintenance. Frontiers in Cellular and Infection Microbiology, 14, 1401963.

[7] Sun, J., Song, F. H., Wu, J. Y., Zhang, L. Q., Li, D. Y., Gao, S. J., … & Mei, W. (2022). Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation. Brain, behavior, and immunity, 102, 53-70.

Date Posted: July 25, 2025

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7,000 Steps a Day Are Enough for Most Benefits

A massive new meta-analysis confirms that 10,000 daily steps are not required for most of the health benefits of walking. Around 7,000 seems to be the sweet spot [1].

A step in the right direction

“10,000 steps a day” is some of the most frequently heard health advice. It is hard to say why this particular number has become the Holy Grail of walking [2], but some recent studies have suggested that there is nothing special about it and that you can get most of the health benefits (and there are many) by clocking less steps [3].

A new review, coming from the University of Sydney and published in the journal Lancet Public Health, summarizes the current state of knowledge by synthesizing data from 57 studies from 2014 to 2025 that were conducted in more than ten countries, including Australia, the US, the UK, and Japan. This makes it the most comprehensive analysis to date on the relationship between daily steps and a wide range of health outcomes.

The sweet spot

For many outcomes, including all-cause mortality, cardiovascular mortality, cardiovascular disease incidence, dementia, and falls, the researchers discovered an inverse non-linear association, with inflection points at around 5000-7000 steps per day. This means that after this threshold, the “return on investment” was diminished. Interestingly, after the plateau at around 7,000 steps a day, all-cause, cardiovascular, and cancer mortality risks took another dip when approaching 12,000 steps.

However, several outcomes showed a linear reduction in risk as step counts increased, without a noticeable plateau. Those included cancer incidence, type 2 diabetes incidence, and the risk of depressive symptoms. The latter relationship was quite strong, suggesting that long walks are indeed good for mental health.

Compared to a baseline of 2,000 steps per day, walking 7,000 steps per day was associated with a 47% lower risk of all-cause and cardiovascular mortality, 25% lower risk of cardiovascular disease incidence, 37% lower risk of cancer mortality, 38% lower risk of dementia, 14% lower risk of type 2 diabetes, 22% lower risk of depressive symptoms, and 28% lower risk of falls. The authors emphasize that even moving from 2,000 to 4,000 steps a day was linked to substantial health benefits, including a 36% lower risk of all-cause mortality.

“Aiming for 7,000 steps is a realistic goal based on our findings, which assessed health outcomes in a range of areas that hadn’t been looked at before,” said Professor Melody Ding from the School of Public Health, a lead author of the study. “However, for those who cannot yet achieve 7,000 steps a day, even small increases in step counts, such as increasing from 2,000 to 4,000 steps a day, are associated with significant health gain. We know daily step count is linked to living longer, but we now also have evidence that walking at least 7,000 steps a day can significantly improve eight major health outcomes – including reducing the risk of cardiovascular disease, dementia and depressive symptoms.”

“For people who are already active, 10,000 steps a day is great,” said Dr. Katherine Owen, co-author and chief analyst of the study from the School of Public Health. “But beyond 7000 steps, the extra benefits for most of the health outcomes we looked at were modest.”

An achievable goal

Populational studies are notoriously noisy and cannot definitively prove causality. Combining data from several studies might be even trickier. While the researchers tried to account for this, they also admit several limitations of their study. One potential problem constantly lurking in such studies is reverse causality: people with health conditions are less capable of or amenable to physical activity, which might partially explain their prevalence in the low-activity part of the spectrum. However, researchers made an honest attempt to control for such confounding factors.

This study adds important knowledge, since 7,000 steps a day is a much more achievable everyday goal than 10,000. This does not mean that people should stop after 7,000 steps, but knowing that it is possible to get most of the health perks of walking with less effort might offer encouragement, especially to populations who might benefit from physical activity the most. “Our research helps to shift the focus from perfection to progress,” says Professor Ding. “Even small increases in daily movement can lead to meaningful health improvements.”

Yes I will donate❤️

Literature

[1] Ding, D., Nguyen, B., Nau, T., Luo, M., del Pozo Cruz, B., Dempsey, P. C., … Owen, K. (n.d.). Daily steps and health outcomes in adults: a systematic review and dose-response meta-analysis. The Lancet Public Health.

[2] Stamatakis, E., Ahmadi, M., Murphy, M. H., Chico, T. J., Milton, K., Cruz, B. D. P., … & Gill, J. (2023). Journey of a thousand miles: from ‘Manpo-Kei’to the first steps-based physical activity recommendations. British Journal of Sports Medicine, 57(19), 1227-1228.

[3] Paluch, A. E., Bajpai, S., Bassett, D. R., Carnethon, M. R., Ekelund, U., Evenson, K. R., … & Fulton, J. E. (2022). Daily steps and all-cause mortality: a meta-analysis of 15 international cohorts. The Lancet Public Health, 7(3), e219-e228.

Date Posted: July 24, 2025

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A Gene That Keeps Cells Under Control

Researchers publishing in Cell Stem Cell have investigated the function of the gene DNMT3A and found that it has wide-ranging effects beyond methylation.

More effects than expected

Clonal hematopoiesis (CH), which occurs when stem cells create large numbers of cells with the same mutation, is linked to blood cancers [1]. DNMT3A is the most commonly mutated gene in CH [2], it has been directly linked to cancer itself [3], and we have previously reported on DNMT3A mutants being able to outcompete unmutated cells in the body.

These researchers note that as DNMT3A has been described as a methyltransferase enzyme due to its function in embryonic stem cells [4], most work has been done on its relationship to methylation. However, other evidence suggests that this function may not be relevant in the context of CH, cancer, and other age-related diseases; the methylation directly affected by DNMT3A may have little to do with the actual downstream consequences of its mutations [5]. The researchers of this study, therefore, wanted to know what this gene does, and does not, actually do in adult organisms.

Methylation-deficient variants still have strong effects

The mouse gene Dnmt3L works with Dnmt3a to methylate DNA. Therefore, in their first experiment, the researchers used lentiviral transduction to overexpress Dnmt3L in blood stem cells (HSPCs) derived from mice along with another group that overexpresses Dnmt3a as well as a control group. As expected, the Dnmt3L group had very different methylation from either group, and overexpressing Dnmt3L in Dnmt3a-deficient cells yielded no statistically significant difference, showing that its effects are dependent on Dnmt3a.

Changing the expression of Dnmt3a, on the other hand, yielded completely different results. Death by apoptosis significantly increased in cells that overexpressed this gene. Cells that did not express Dnmt3a reproduced out of control, creating far more colony-forming units. By creating Dnmt3a variants that had impaired methylation activity, the researchers ascertained that its restraining effects are not due to methylation. Cells that had one of these variants had far less methylation than cells with normal Dnmt3a, yet their reproduction was equally controlled.

Mouse experiments found that, while some level of DNA methylation is required for normal embryonic development, the low-methylation variants did not have significant amounts of CH compared to wild-type cells when given as transplants to irradiated mice. Further experimentation involving transplants found that cells that don’t express Dnmt3a at all were significantly tilted towards self-renewal, while the methylation-affected variants were more restrained.

Concordant with their other experiments, the researchers analyzed the effects of these variants and found that function and methylation had no significant correlations. This even extended to gene expression, which would theoretically be directly related; instead, gene expression and methylation had no significant correlation in this experiment.

Effects on telomeres and reproduction

Previous work has also found that Dnmt3a loss is linked to longer telomeres in mice [7] and that DNMT3A mutations are linked to lengthened telomeres in cancers in people [8]. Therefore, the researchers examined the telomeres of their transplanted cells and found that this is indeed the case; both telomere length and the telomere-lengthening gene Tert were increased in cells that do not express Dnmt3a. This length was also increased in the short term in the methylation-impaired variants but was reduced over time, suggesting both methylation-related and unrelated mechanisms.

A lack of Dnmt3a was also found to keep cells proliferating when telomere-related mechanisms suggested that they should not. The DNA damage response is activated when telomeres become too short, causing senescence; however, a lack of Dnmt3a was found to cause these cells to continue to proliferate, and this had nothing to do with methylation. Furthermore, both telomerase and alternative mechanisms of lengthing telomeres were caused by a lack of Dnmt3a.

This study illuminates key facts about cellular senescence and proliferation. Uncontrolled growth is perhaps even more immediately dangerous in the context of aging than unwelcome senescence. The proliferation of unhealthy cells is a driving force behind cancer and other age-related diseases, and this study may be followed up by future work that seeks to restore DNMT3A in order to stop runaway clonal expansion of mutated cells.

Yes I will donate❤️

Literature

[1] Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., … & Ebert, B. L. (2014). Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine, 371(26), 2488-2498.

[2] Challen, G. A., & Goodell, M. A. (2020). Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood, The Journal of the American Society of Hematology, 136(14), 1590-1598.

[3] Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., … & Wilson, R. K. (2010). DNMT3A mutations in acute myeloid leukemia. New England Journal of Medicine, 363(25), 2424-2433.

[4] Okano, M., Xie, S., & Li, E. (1998). Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature genetics, 19(3), 219-220.

[5] Spencer, D. H., Russler-Germain, D. A., Ketkar, S., Helton, N. M., Lamprecht, T. L., Fulton, R. S., … & Ley, T. J. (2017). CpG island hypermethylation mediated by DNMT3A is a consequence of AML progression. Cell, 168(5), 801-816.

[6] Jia, D., Jurkowska, R. Z., Zhang, X., Jeltsch, A., & Cheng, X. (2007). Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature, 449(7159), 248-251.

[7] Gonzalo, S., Jaco, I., Fraga, M. F., Chen, T., Li, E., Esteller, M., & Blasco, M. A. (2006). DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nature cell biology, 8(4), 416-424.

[8] Myllymäki, M., Redd, R., Reilly, C. R., Saber, W., Spellman, S. R., Gibson, C. J., … & Lindsley, R. C. (2020). Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome. Blood, The Journal of the American Society of Hematology, 136(26), 3070-3081.

Date Posted: July 23, 2025

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Organ-Specific Aging Analysis Reveals Disease Connections

A recent study explored the differences in the speed of organ aging. The researchers have built models that can predict the odds of diseases and mortality risk based on organ-specific proteins found in plasma [1].

Not all organs age equally

Since each organ in the human body is different, the way they age also differs, with some ceasing to function properly early in life, such as the female reproductive system. Monitoring organ health and developing interventions to improve individual organs may be a viable approach to extend healthspan and lifespan.

In this study, the researchers estimated the biological age of 11 organs: adipose tissue, artery, brain, heart, immune tissue, intestine, kidney, liver, lung, muscle, and pancreas. They used data from the UK Biobank, analyzing almost 3,000 proteins found in the plasma of over 44,000 people between the ages of 40 and 70 years.

First, they defined which plasma proteins were likely to be derived from a specific organ. Based on this data, they trained models to predict participants’ biological age for each organ separately. Their results suggested organ-specific differences in biological age that were only weakly correlated with each other, implying that organs age at different rates.

Organ age estimates allowed the researchers to predict future diseases in specific organs, including highly significant associations between heart aging and atrial fibrillation (irregular and rapid heart rhythms) and heart failure, pancreatic aging and kidney aging with chronic kidney disease, brain aging with Alzheimer’s disease, and lung aging with chronic obstructive pulmonary disease (COPD).

“We’ve developed a blood-based indicator of the age of your organs,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences and director of the Knight Initiative for Brain Resilience. “With this indicator, we can assess the age of an organ today and predict the odds of your getting a disease associated with that organ 10 years later.”

An extremely young brain is protective against dementia

Since the organs didn’t age at the same speed, the researchers turned to look at ‘extreme organ agers’ who had one or more organs that aged much faster along with another group of people who had extremely youthful organs.

Extreme agers of 2 to 4 organs had a significantly elevated risk for every disease examined by the researchers. On the other side, people who had between 2 and 4 extremely youthful organs were protected from many diseases.

The researchers evaluated the speed of brain aging and Alzheimer’s association more deeply. They learned that extreme brain aging led to a 3.1-fold increase in the risk of Alzheimer’s disease. In contrast, an extremely young brain reduced the risk by 74% independent of age, sex, APOE4 (a strong genetic risk factor for Alzheimer’s), and APOE2 (a genetic variant linked to lower Alzheimer’s risk). As they conclude in the paper, “individuals with aged brains exhibited a 13.5-fold increased risk of developing Alzheimer’s disease compared to those with youthful brains.”

To put this risk in perspective, the researchers compared it to the APOE genotype. The risk of developing Alzheimer’s for a person with an aged brain was similar to carrying one copy of APOE4. In contrast, a youthful brain was as protective as carrying two copies of APOE2. Brain age was very weakly correlated with APOE genotype.

The brain as a central lifespan regulator

The researchers also found a link between organ biological age and mortality risk, with brain aging having the most potent predictive properties, “suggesting that the brain may be a central regulator of lifespan in humans“.

The researchers note an association between each organ age and the risk of death. An aged single organ was associated with a 1.5- to 3-fold increased risk of death, and having more aged organs led to an even higher risk of death. Having 2-4, 5-7, or 8+ extremely aged organs was associated with a 2.3-fold, 4.5-fold, and 8.3-fold increased risk of death, respectively.

Surprisingly, youthful organs were not protective regarding mortality risk, and the researchers were not clear about the reasons behind this. They suggest that the sample size might have been too small to see statistically significant differences.

A significant reduction in mortality risk was observed only in participants with youthful brains and immune systems. This brain- and immune-system-related longevity was probably due to the preservation of the brain extracellular matrix, which was caused by reduced degradation by peripheral inflammatory factors and reduced chronic inflammation.

“The brain is the gatekeeper of longevity,” Wyss-Coray said. “If you’ve got an old brain, you have an increased likelihood of mortality. If you’ve got a young brain, you’re probably going to live longer.”

This seems unsurprising, given that the brain regulates many age-related bodily functions, such as circadian rhythms, blood pressure, energy homeostasis, and stress response. The immune system is also linked to aging processes, with a strong role of chronic inflammation in aging.

Lifestyle matters for organ aging

The researchers tested 18 lifestyle factors, such as diet, alcohol, smoking, exercise, and insomnia; socioeconomic factors, including education and the Townsend Deprivation Index, a metric of material deprivation; and 137 drugs and supplements, adjusted for each other, age, and sex.

The researchers reported an association between age acceleration across several organs and smoking, alcohol, processed meat intake, the Townsend Deprivation Index, and insomnia. Youthful organs were found to be associated with vigorous exercise, oily fish consumption, poultry consumption, and higher education. Premarin, ibuprofen, glucosamine, cod liver oil, multivitamins, and vitamin C were significantly associated with youth in at least two organs.

Premarin’s association was especially interesting, since Premarin is an estrogen medication used by women experiencing postmenopausal symptoms. Observing this, the researchers asked whether the timing of menopause might impact organ aging, thus affecting lifespan and disease risk. Among the small sample of women they were able to analyze, they noted an association between earlier menopause and accelerated aging across most organs, while estrogen treatment was associated with youthful immune, liver, and artery profiles.

Preventing organ-specific diseases

The researchers would like to expand on this topic by, for example, defining the sequence of organ aging for individuals and on the population level. It would also be interesting to delve deeper into sex-specific differences since the data showed that men had older kidneys, immune systems, and intestines than women, while women’s adipose tissue, arteries, and hearts were older than men’s.

The authors hope that these tools can help to monitor organ health and to test organ-specific medical interventions that could expand longevity. “This approach could lead to human experiments testing new longevity interventions for their effects on the biological ages of individual organs in individual people,” Wyss-Coray said.

Yes I will donate❤️

Literature

[1] Oh, H. S., Le Guen, Y., Rappoport, N., Urey, D. Y., Farinas, A., Rutledge, J., Channappa, D., Wagner, A. D., Mormino, E., Brunet, A., Greicius, M. D., & Wyss-Coray, T. (2025). Plasma proteomics links brain and immune system aging with healthspan and longevity. Nature medicine, 10.1038/s41591-025-03798-1. Advance online publication.

Date Posted: July 22, 2025

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FDA-Approved Drug Combo Rescues Alzheimer’s in Mice

Scientists have creatively used large databases of existing FDA-approved drugs and electronic medical records to locate candidates that are potentially effective against Alzheimer’s [1].

New approaches needed

Many previously discovered drugs may be effective beyond their original indications, but it is challenging to match them to new ones. Thankfully, ever-growing computing power, new data, and novel analytical tools make repurposing drugs easier.

In a new study published in the journal Cell, scientists from the University of California San Francisco set out to find existing drugs that would be effective against Alzheimer’s disease. Billions of dollars have been poured into Alzheimer’s drug development, but successes are very rare. Even a handful of the particularly expensive drugs that have been approved only slightly delay the disease’s progression, which makes finding new therapeutic options a pressing need.

One problem is Alzheimer’s complex etiology. Scientists do not know the exact causes, but it seems to be an amalgam of many factors, such as the accumulation of amyloid-β and tau proteins along with neuroinflammation [2]. To complicate things further, various types of brain cells behave differently in this disease.

Different cells, different drugs

The researchers used data from three large, publicly available single-nucleus RNA sequencing (snRNA-seq) datasets from human post-mortem brain tissue to determine which proteins are expressed differently in Alzheimer’s-affected brains vs healthy brains. Gene expression changes in six major brain cell types were included in the analysis: excitatory neurons, inhibitory neurons, microglia, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells (OPCs).

The team found that each cell type had a unique Alzheimer’s-related gene expression signature, with some genes showing opposite changes in different cell types. For example, in people with Alzheimer’s, the well-known risk-related gene APOE was upregulated in microglia but downregulated in astrocytes and OPCs.

The next step was to find existing drugs that could reverse these changes. The researchers used the Connectivity Map (CMap), a database of gene expression changes in human cell lines caused by different drugs, to screen for potential therapeutic candidates. By looking for molecules that produced gene expression changes in opposition to the Alzheimer’s signatures for each cell type, they identified several potential hits.

25 repurposed drugs significantly reversed cell-type-specific Alzheimer’s-associated gene expression profiles in multiple cell types. The list included a wide variety of compounds, such as antibiotics, anti-inflammatories, and antipsychotics. The immunosuppressant rapamycin (sirolimus), known for its anti-aging properties, also made the cut.

The team then validated their findings using a large Electronic Medical Records (EMR) database from the University of California health system by assessing the risk of Alzheimer’s in patients who had been prescribed these drugs for other conditions, such as cancer, to a matched control group with similar demographic and health characteristics.

The researchers decided to move on with two compounds, letrozole and irinotecan, as a combination therapy. Letrozole is a hormone therapy used for breast cancer, while irinotecan is a chemotherapy drug.

Letrozole was chosen to target neuronal Alzheimer’s signatures, and irinotecan is for glial cell signatures. The EMR analysis revealed that both were associated with a significantly lower risk of Alzheimer’s. Letrozole showed a relative risk of 0.466, while irinotecan had a risk of 0.195, meaning that patients who took irinotecan had an 80.5% lower risk of being diagnosed with Alzheimer’s compared to their matched control group.

“Alzheimer’s is likely the result of numerous alterations in many genes and proteins that, together, disrupt brain health,” said Yadong Huang, MD, Ph.D., senior investigator and director of the Center for Translational Advancement at Gladstone, professor of neurology and pathology at UCSF, and co-senior author of the paper. “This makes it very challenging for drug development – which traditionally produces one drug for a single gene or protein that drives disease.”

Sex-specific effects in mice

For in vivo validation, the researchers used a mouse model (5xFAD/PS19) that develops both amyloid plaques and tau tangles, the two key pathologies of AD, to closely mimic the human condition. The mice were treated for three months with either letrozole, irinotecan, or their combination.

The team assessed the mice’s spatial learning and memory using the Morris water maze test. Only the mice on the combination therapy demonstrated a significant improvement in both short-term and long-term memory compared to controls. The single-drug treatments produced much less pronounced effects.

The effect was also sex-dependent, with female mice showing much less improvement in the tests. Interestingly, letrozole works by targeting the estrogen pathway, which might explain the disparity. It is also known that in humans, Alzheimer’s prevalence is much higher in women, although this might be due to their longer average life expectancy [3]. On the other hand, EMR analysis showed no sex differences in letrozole’s effect on Alzheimer’s prevalence. The authors caution, however, that this finding is inconclusive because the number of male patients taking letrozole was very small.

After the behavioral tests, the researchers examined the mice’s brains for Alzheimer’s-related pathologies. The combination therapy group showed significant reductions in hippocampal atrophy, amyloid-beta plaque load, phosphorylated tau (p-tau) pathology, neuroinflammation, and neuronal loss. The treatment also reversed the expression of many of the disease’s signature genes that were initially identified in humans.

“Alzheimer’s disease comes with complex changes to the brain, which has made it tough to study and treat, but our computational tools opened up the possibility of tackling the complexity directly,” said Marina Sirota, Ph.D., the interim director of the UCSF Bakar Computational Health Sciences Institute, professor of pediatrics, and co-senior author of the paper. “We’re excited that our computational approach led us to a potential combination therapy for Alzheimer’s based on existing FDA-approved medications.”

Yes I will donate❤️

Literature

[1] Li, Y., Pereda Serras, C., Blumenfeld, J., Xie, M., Hao, Y., Deng, E., … Sirota, M. (n.d.). Cell-type-directed network-correcting combination therapy for Alzheimer’s disease. Cell.

[2] Breijyeh, Z., & Karaman, R. (2020). Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules, 25(24), 5789.

[3] Mielke, M. M. (2018). Sex and gender differences in Alzheimer’s disease dementia. The Psychiatric times, 35(11), 14.

Date Posted: July 21, 2025

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Vesicles From Antler Cells Restore Bone in Monkeys

Researchers publishing in Nature Aging have discovered that extracellular vesicles (EVs) derived from antler blastema progenitor cells (ABPCs) restore bone mass to rhesus macaques.

Finding the most effective EVs

In the world of rejuvenation research, EVs are nothing new. We have covered them extensively, as studies have repeatedly found benefits for the heart and effectiveness against cellular senescence. Because they are derived from stem cells rather than being cells themselves, there are no concerns with immunorejection [1].

Deer antlers are the only organ that regenerates fully in adulthood, and so antler cells have been an attractive source of pro-regeneration EVs. One study found that ABPCs remain robust even after 50 cellular cycles and that their EVs are a potential treatment for arthritis [2]. These researchers have previously found a population of ABPCs with particularly strong potential [3]; this study uses those cells’ EVs against multiple age-related targets.

More effective than bone marrow cells

In their first experiment, the researchers compared their ABPCs to bone marrow stem cells (BMSCs) derived from aged and fetal rats. The ABPCs proliferated far faster than either BMSC group, growing at a rate nearly six times that of the adult cells and over three times as fast as the fetal cells. They had significantly lower senescence markers as well. These differences were due to cell type rather than species; BMSCs derived from young male deer had roughly the same proliferation rates as fetal rat BMSCs.

ABPCs also produced more EVs than BMSCs, producing almost ten times as many as adult BMSCs and twice as many as fetal BMSCs. An RNA analysis of ABPC-derived EVs found many beneficial factors, including directly pro-regeneration factors along with maintenance of the cell cycle, telomere length and proteostasis. Inflammatory factors were downregulated in these EVs, and they were better than fetal BMSCs at promoting cellular function.

ABPC-derived EVs were more effective than fetal BMSC-derived EVs in attenuating aging in adult BMSCs. Compared to the fetal group, the ABPC group had far less of the DNA damage marker γ-H2AX, greatly reduced senescence markers, and significantly more proliferation. Additionally, aging causes BMSCs to shift from bone to fat, a cause of age-related bone loss; ABPC-derived EVs were more effective than BMSC-derived EVs in reversing this tendency.

The researchers identified a single, crucial mRNA in EVs that was responsible for a substantial portion of this effect: Prkar2a, which is involved in the cell cycle and in cellular development. Adult ABPCs that had impaired response to Prkar2a received far fewer benefits.

Effective in mice

The researchers then administered the various EVs to aged mice for four weeks. Here, again, ABPCs outperformed the other groups, substantially increasing bone strength and mineral density. While osteoclasts, which degrade bone, were similar among all the tested groups, the ABPC group had much more osteoblast activity, which represents more bone formation.

Once more, isolating Prkar2a had substantial benefits: removing it from ABPC-derived EVs significantly diminished their effectiveness, while adding it to adult BMSC-derived EVs greatly enhanced theirs.

There were also substantial systemic benefits from ABPC-derived EV administration. Mice given these EVs had better balance and less fatigue along with a reduction in SASP-related inflammatory markers such as interleukins. Gene expression related to oxidative stress was reduced, and epigenetic aging markers showed evidence of rejuvenation in this area as well.

There were multiple benefits across multiple organs. The ABPC EV-treated mice’s kidneys had less evidence of cellular death by apoptosis, and their livers and kidneys had less fibrosis. There was also a neuroprotective effect, as these mice’s brains had less evidence of DNA damage. Systemic benefits were found in both male and female mice.

The effects on the brain were examined more closely, and the researchers found evidence of better brain function; the treated mice were more interested in new things, as measured by the Y maze test and the novel object recognition test. They also spent more time in the open arms in an elevated maze, suggesting reduced anxiety.

Monkeys received benefits as well

Because of their similarity to human beings, non-human primates, such as the rhesus macaques used in this study, are commonly used to test the effectiveness of promising approaches. Compared to a control group that only received saline, treating older female monkeys with ABPC-derived EVs greatly increased their willingness to move without affecting their ability to sleep. Improvements in motor dexterity were also noted.

The benefits to cellular function found in mice were also observed in these monkeys. Prkar2a was upregulated, inflammatory cytokines and senescent cells were reduced, and epigenetic age was reduced in bone marrow. While the monkeys’ intelligence was not analyzed, brain imaging found substantial improvements to their grey matter, including in the cerebral cortex.

While the researchers do not yet recommend their ABPC-derived EVs for human use, suggesting that there may be a possibility of tumors over the long term, they note that their findings provide a foundation for potential treatments. It may be possible to isolate the key factors that make ABPC-derived EVs so effective, such as Prkar2a, and administer them directly.

Yes I will donate❤️

Literature

[1] Zhang, K., & Cheng, K. (2023). Stem cell-derived exosome versus stem cell therapy. Nature Reviews Bioengineering, 1(9), 608-609.

[2] Lei, J., Jiang, X., Li, W., Ren, J., Wang, D., Ji, Z., … & Wang, S. (2022). Exosomes from antler stem cells alleviate mesenchymal stem cell senescence and osteoarthritis. Protein & cell, 13(3), 220-226.

[3] Qin, T., Zhang, G., Zheng, Y., Li, S., Yuan, Y., Li, Q., … & Qiu, Q. (2023). A population of stem cells with strong regenerative potential discovered in deer antlers. Science, 379(6634), 840-847.

Date Posted: July 18, 2025

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AI Reveals a Hidden Effect in a Failed Alzheimer’s Trial

Scientists have created an AI model that stratifies Alzheimer’s patients into subgroups that progress slowly or rapidly. When applied to a real-world failed trial, it revealed a robust effect in the former subgroup [1].

Stratify and conquer

Drugs don’t work for everyone equally. Unfortunately, clinical trials are not always able to account for that, which creates several potential problems: what if a drug shown to be ineffective in a trial actually works for a subset of patients? How do we identify this subset and make sure that a useful treatment does not get discarded?

Scientists have suspected for quite a while that this is the case for some experimental treatments for Alzheimer’s disease (AD). The success rate in AD trials is abysmal. Might this be due to the heterogeneity of the patient population?

In a new study from the University of Cambridge, published in Nature Communications, scientists trained their Predictive Prognostic Model (PPM) on data from the ADNI (Alzheimer’s Disease Neuroimaging Initiative) study in order to differentiate their subgroups. The sample size (256 patients) and the number of parameters (just three: β-amyloid, APOE4, and medial temporal lobe grey matter density), were rather small, but according to the authors, it was enough to achieve 91.1% classification accuracy.

The hidden effect

The team then applied their tool to AMARANT, a real-world clinical trial that had failed to show efficacy of lanabecestat, a BACE1 inhibitor designed to reduce the production of β-amyloid plaques in the brain. The AI model analyzed each patient’s baseline data and assigned a prognostic score with which to judge the progression of Alzheimer’s.

“Our AI model gives us a score to show how quickly each patient will progress towards Alzheimer’s disease,” said Professor Zoe Kourtzi in the University of Cambridge’s Department of Psychology, senior author of the study. “This allowed us to precisely split the patients in the clinical trial into two groups: slow- and rapid-progressing, so we could look at the effects of the drug on each group.”

When the researchers analyzed the drug’s efficacy for the slow-progressing subgroup, they found a 46% slowdown in the disease’s progression in patients that received the higher 50mg dose. This is significantly more than what the best treatments that passed their trials achieved for the entire patient population. When the researchers lumped the subgroups back together, the cognitive benefit disappeared, confirming the original outcome and proving that the effect was masked by the heterogeneity of the initial trial population.

Alzheimer’s escape velocity

The team then asked another question: did the treatment prevent patients from transitioning from slow progress to more rapid progress? The answer was positive, as high-dose lanabecestat kept patients in the slow-progressing, hence probably more treatable, subgroup for longer. For the placebo group, 60% of “slow progressors” transitioned to “rapid,” while for the 50mg lanabecestat group, only 33.3% did.

This outcome might be highly relevant considering that new treatments for dementia are nearing approval and will likely be more effective in slowly progressing patients. Combined with better early-stage diagnostics, this might create a sort of “Alzheimer’s escape velocity,” when one treatment slows the disease’s progression enough for upcoming treatments to take over.

“AI can guide us to the patients who will benefit from dementia medicines, by treating them at the stage when the drugs will make a difference, so we can finally start fighting back against these cruel diseases,” said Kourtzi. “Making clinical trials faster, cheaper and better, guided by AI, has strong potential to accelerate the discovery of new precise treatments for individual patients, reducing side effects and costs for health care services.”

Cheaper trials

Stratifying patients with this new AI tool from the start might help make Alzheimer’s clinical trials cheaper and likelier to succeed. The researchers calculated that to detect the drug’s effect in an AI-selected slowly progressing group, a future trial would only need 82 patients per group (treatment vs. placebo). In contrast, to find an effect in a mixed group, a trial would require 762 patients per group. This amounts to a 90% reduction in the required sample size, which could save hundreds of millions of dollars and years of time in drug development. This might seem like abandoning the rapid-progressing patient population, but as this study shows, many of them are former “slow progressors.”

“Promising new drugs fail when given to people too late, when they have no chance of benefiting from them,” Kourtzi said. “With our AI model, we can finally identify patients precisely and match the right patients to the right drugs. This makes trials more precise, so they can progress faster and cost less, turbocharging the search for a desperately needed precision medicine approach for dementia treatment.”

Literature

[1] Vaghari, D., Mohankumar, G., Tan, K., Lowe, A., Shering, C., Tino, P., & Kourtzi, Z. (2025). AI-guided patient stratification improves outcomes and efficiency in the AMARANTH Alzheimer’s Disease clinical trial. Nature Communications, 16(1), 1-12.

Date Posted: July 17, 2025

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Engineered Stem Cells Reduce Lung Fibrosis in Mice

In Molecular Therapy, researchers have described their creation of cells that express the regenerative factor GDF11 and found that they ameliorate fibrosis in a mouse model.

Context-dependent benefits

Like sirtuins and klotho, GDF11 is a biochemical factor that has been heavily investigated in the context of age-related diseases [1]. However, research on it has been contradictory, with some research finding that it is detrimental for muscle regeneration [2] and other research finding that it is beneficial [3]. Some research has found that GDF11 mitigates fibrosis [4], while other research has found that it causes it [5].

These researchers offer several explanations as to why. There are measurement problems involving its similarity to GDF8, but its effects are also extremely context-dependent, varying by dose, disease, fibrosis amount, and tissue type [6].

All of these caveats, along with GDF11’s high cost of manufacture and short half-life in the body, make using it as a drug extremely difficult. The proper dose at the right time may provide significant benefits, but improper dosing can be very dangerous [7].

Therefore, these researchers have developed an embryonic stem cell (ESC) line that endogenously produces GDF11 and can be triggered to secrete it. They differentiated lung progenitors from these engineered cells, which have been made safer with a kill switch that removes harmful cells that proliferate too rapidly [8].

Beneficial for lung cells

In their first experiment, the researchers confirmed that older mice express the Gdf11 gene much less than their younger counterparts. Interestingly, 12-month-old and 24-month-old mice do not differ much in this respect, and so 12-month-old mice were chosen as the “old” group in future experiments; the young mice they were compared to were only 8 to 10 weeks old.

Some of these mice were subjected to a lung injury that involes bleomycin, which induces fibrosis. This is a well-known model that mimics idiopathic pulmonary fibrosis (IPF) in human beings. Unsurprisingly, the older mice could not recover from fibrosis 28 days after bleomycin exposure in the same way that the young mice did.

This injury decreased Gdf11 exposure in the old mice compared to healthy age-matched controls. The researchers also discovered a negative association between Gdf11 and the fibrosis gene S100a4, a gene that was accompanied by an increase in the senescence-related gene p16.

The researchers then returned to cells, examining alveolar type II cells (AEC-IIs) that reside in the distal lung. Exposing old AEC-11s to recombinant GDF11 restored their expression of surfactant protein C, which is vital for these cells’ function, and restored mitochondrial function as well, reducing the effects of oxidative stress.

The telomeres of these AEC-11s were lengthened by GDF11 as well, and there were no effects in this respect on young cells. DNA damage appeare to be reduced, and senescence genes were reduced as well. This was accomplished without killing the senescent cells, making GDF11 a senomorphic compound rather than a senolytic one for these cells.

Then, the researchers further described the cells they had created for this study. They made sure that these particular cells were committed to being lung progenitors and that they would only produce GDF11 when prompted to do so by the administration of doxycycline, a drug that does not occur in nature. These cells were designated as SC-GDF11 cells.

The researchers then compared what happens to bleomycin-injured lung cells in the presence of either recombinant GDF11 or SC-GDF11 cells and doxycycline, along with other groups cultured alongside other cells that did not express GDF11. Compared to those groups, the GDF11-exposed cells fared much better, with significantly reduced signs of cellular senescence; the SC-GDF11 cells were even more effective than the recombinant GDF11.

Significantly reduced fibrosis in mice

Finally, the researchers tested their cells in older mice. Two weeks after bleomycin administration, they administered SC-GDF11 cells to one population, alongside a group that received cells that do not express GDF-11 along with a bleomycin-only group and a control group with uninjured lungs. The lungs of the SC-GDF11-treated mice looked much more like those of the control group compared to the non-GDF11 groups, with normal alveola and lung density along with far less fibrosis. The treatment group’s lungs were also able to inhale normal amounts of air, demonstrating a preservation of function.

These findings were confirmed with a gene expression analysis. Not only was Gdf11 restored, a variety of key senescence markers, including those responsible for the senescence-associated secretory phenotype (SASP), were significantly reduced, with some markers at the levels of the control group and others only slightly above it.

In total, these are strong results that suggest that this is a potential treatment. Of course, this is still only a murine and cellular study, the created cells were made for mice rather than human beings, and bleomycin-induced injury is still only a model of IPF. There is also a question of immune rejection; although the researchers have a potential remedy to this problem [9], it was not implemented in this particular study. Therefore, further work on designing cells for human use must be done before clinical trials can begin.

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Literature

[1] Zhang, Y., Wei, Y., Liu, D., Liu, F., Li, X., Pan, L., … & Chen, D. (2017). Role of growth differentiation factor 11 in development, physiology and disease. Oncotarget, 8(46), 81604.

[2] Egerman, M. A., Cadena, S. M., Gilbert, J. A., Meyer, A., Nelson, H. N., Swalley, S. E., … & Glass, D. J. (2015). GDF11 increases with age and inhibits skeletal muscle regeneration. Cell metabolism, 22(1), 164-174.

[3] Sinha, M., Jang, Y. C., Oh, J., Khong, D., Wu, E. Y., Manohar, R., … & Wagers, A. J. (2014). Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science, 344(6184), 649-652.

[4] Dai, Z., Song, G., Balakrishnan, A., Yang, T., Yuan, Q., Möbus, S., … & Sharma, A. D. (2020). Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells. Gut, 69(6), 1104-1115.

[5] Pons, M., Koniaris, L. G., Moe, S. M., Gutierrez, J. C., Esquela-Kerscher, A., & Zimmers, T. A. (2018). GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure. Surgery, 164(2), 262-273.

[6] Zhang, F., Yang, X., & Bao, Z. (2022). Bioinformatics network analyses of growth differentiation factor 11. Open Life Sciences, 17(1), 426-437.

[7] Sutherland, B. A., Hadley, G., Alexopoulou, Z., Lodge, T. A., Neuhaus, A. A., Couch, Y., … & Buchan, A. M. (2020). Growth differentiation factor-11 causes neurotoxicity during ischemia in vitro. Frontiers in Neurology, 11, 1023.

[8] Liang, Q., Monetti, C., Shutova, M. V., Neely, E. J., Hacibekiroglu, S., Yang, H., … & Nagy, A. (2018). Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature, 563(7733), 701-704.

[9] Pavan, C., Davidson, K. C., Payne, N., Frausin, S., Hunt, C. P., Moriarty, N., … & Parish, C. L. (2025). A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models. Cell Stem Cell, 32(5), 710-726.

Date Posted: July 17, 2025

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Immortal Dragons Launches $40M Longevity Fund

Immortal Dragons, a purpose-driven longevity fund headquartered in Singapore, today announced its unique approach to investing in radical life extension technologies. With $40 million in assets under management (AUM), Immortal Dragons is poised to redefine how capital fuels scientific breakthroughs in longevity and healthspan.

At its core, Immortal Dragons is driven by a profound philosophy: to view aging and death not as inevitability, but as technical challenges that can be overcome through scientific innovation. This conviction underpins every investment decision, prioritizing impacts over financial returns.

Moonshot Ventures

Immortal Dragons targets diverse areas within the longevity sector. The fund has already invested in over 15 startups that are at the forefront of these paradigm shifts, exploring technologies across several strategic pillars:

Replacement & Regeneration: Including pioneering research in xenotransplantation, cryopreservation, replacement or regeneration of biological components.
Gene Therapy: Gene therapies aimed at addressing the root causes of aging and age-related diseases.
3D Bioprinting: 3D bioprinting of tissues and organs for therapeutic and regenerative purposes.
Longevity Infrastructure: Foundational ecosystem for longevity science, accelerated clinical trials, and regulatory sandboxes.

Boyang Wang, the founder of Immortal Dragons, articulated the fund’s approach: “Whether it’s cutting-edge science or creating better environments for research, we need to see the opportunity for real impact.” [2] This commitment to diverse areas guides the fund towards supporting what Boyang calls “moonshot projects push the boundaries of science, while infrastructure work – like special economic zones – creates conditions for broader success.” [2]

Purpose-Driven Capital

Operating with the flexibility of a single-LP structure, Immortal Dragons directs its own capital towards projects it is most passionate about, enabling swift and decisive action. This model allows the fund to support underfunded but transformative research that traditional venture capital might overlook.

“We say we are a purpose-driven fund, and the key implication is that Immortal Dragons values impact over economic returns,” Boyang explained in his recent interview. “I’m investing in the field of longevity because I want to see progress and breakthroughs in the sector.” [1]

This commitment extends to personal conviction. Boyang Wang is notably among the first 300 global recipients of Minicircle’s follistatin gene therapy, underscoring the fund’s willingness to embrace and test frontier science. “The gene therapy is a personal attempt, but this does reflect our risk profile and support for the cause,” Boyang explained, “We have strong motivation to support the first wave of longevity companies to make profit, so as to propel the investment flywheel.”

Global Longevity Advocacy

Beyond conventional investments, Immortal Dragons is dedicated to fostering a global longevity advocacy. The fund actively engages in educational outreach, and community-building initiatives, such as translating scientific talks, translating and publishing longevity-themed books, hosting leading chinese longevity podcast channel, sponsorships and grants to longevity initiatives like Vitalist Bay, ARDD 2025. This approach recognizes that progress requires not only financial investment but also public awareness and a robust infrastructure.

The fund’s advocacy approach has been praised by leading academics in the field.

Professor Peter Lidsky of the City University of Hong Kong’s Biomedical Science department commented, “I was excited to meet Immortal Dragons team members at the Vitalist Bay, Berkeley earlier this year. These are young, brave and energetic people committed to resolving the main challenge humanity faces: aging. Their foundation helped me a lot in translating one of my lectures to Chinese, and I hope our collaboration will prosper in the future.”

With deep roots in both east and west, the fund is committed to bridge markets, capital, research and institution through various evangelism efforts.

Aubrey de Grey, president of the LEV Foundation commented, “It has been a great pleasure to get to know the Immortal Dragons team. I have been frustrated for many years that there has been too little longevist activity in China, and I am delighted that that is now changing, with the work of a group that is bringing my and others’ work to the Chinese public. I am also very happy that Immortal Dragons are investing in promising longevity startups.”

Immortal Dragons stands as a testament to the power of purpose-driven investment. By differentiating from the status quo and offering a new perspective to human healthspan, the fund is on a mission to push boundaries and carry on the torch or human life extension.

About Immortal Dragons:

Immortal Dragons (https://www.id.life/) is a purpose-driven longevity fund headquartered in Singapore. The fund invests in cutting-edge, high impact technologies by supporting 15+ portfolio companies. Beyond conventional investments, the fund also puts effort into longevity advocacy, including: book translation and publishing, translation of longevity leader’s talks, hosting leading Chinese longevity podcast, sponsorships and grants to longevity initiatives and conferences.

Contact:

Boyang Wang

Founder of Immortal Dragons

Mailto: contact@id.life

Yes I will donate❤️

References:

[1] Lifespan.io. (2025, June 9) Boyang Wang on Targeting Underfunded Longevity Projects. https://www.lifespan.io/news/boyang-wang-on-targeting-underfunded-longevity-projects

[2] Longevity.Technology. (2025, June 30). Inside the longevity fund that aims to ‘make death optional’. https://longevity.technology/news/inside-the-longevity-fund-that-aims-to-make-death-optional/

Date Posted: July 16, 2025

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A Hallucinogenic Mushroom Compound Extends Mouse Lifespan

Researchers investigated psilocybin, a psychedelic compound found in hallucinogenic mushrooms, for its anti-aging properties. They found that it extends cellular and organismal lifespan, even when administered later in life [1].

From ancient times to contemporary therapies

Hallucinogenic mushrooms have a long history of use, reaching back to ancient times when people often used them for religious or spiritual reasons. Today, their naturally occurring psychedelic compound, psilocybin, has been investigated for its therapeutic value, especially in psychiatric and neurodegenerative diseases [2, 3].

“There have been a number of clinical studies that have explored the therapeutic potential of psilocybin in psychiatric conditions such as depression and anxiety; however, few studies have evaluated its impacts outside the brain,” said Dr. Louise Hecker, associate professor of medicine at Baylor and senior author of the study.

Extending cellular lifespan

Those researchers set out to test the effect of psilocybin on biological aging. In their cell culture studies, they used psilocin, the active metabolite of psilocybin and a product of psilocybin digestion.

First, they tested replicative senescence using human fetal lung fibroblasts. In these experiments, cells were allowed to grow and divide in the presence of psilocin until they reached replicative senescence and became unable to divide further.

Cells treated with higher doses of psilocin had cellular lifespan extended by 57% compared to untreated controls. Treated cells also had delayed senescence; decreased levels of cell cycle arrest, DNA damage, oxidative stress, and senescence markers; increased markers of proliferation and DNA replication; and increased levels of Sirtuin 1, a protein that plays an essential role in aging, metabolism, and stress responses.

Based on their results and the results of previous studies, the authors suggest that psilocybin, through interaction with serotonin receptors, induces the expression of the Sirtuin 1 gene (SIRT1), which increases antioxidant enzymes, leading to a reduction of oxidative stress and neuroprotection. Additionally, SIRT1, through the regulation of senescence, extends longevity.

These results suggest that psilocin impacts multiple aging-associated signaling pathways and processes, leading to delayed senescence and increased cellular lifespan.

The psilocybin-telomere hypothesis

This study was also the first to show experimental evidence supporting the “psilocybin-telomere hypothesis,” [4] which states that psilocybin can positively impact telomere length.

When cultured cells reached the senescent state, the untreated cells had reduced telomere length compared to young cells. However, that did not happen in psilocin-treated age-matched cells, which preserved their telomere length.

While these results shed light on the age-related molecular pathways affected by psilocybin, future studies are necessary to dive deeper to understand the molecular mechanism behind the positive impact of psilocybin on aging-related phenotypes and investigate some pathways and molecular processes that were not examined in this study, including the possible geroprotective impact of psilocybin on epigenetic changes, especially since psychedelic treatments were previously linked to chromatin remodeling and DNA methylation [5, 6].

Improved survival

The positive results of the cellular experiments prompted the researchers to test the effects of psilocybin on mice. They used aged (19-month-old) female mice, equivalent to 60-65 human years, and treated them with psilocybin once per month for 10 months, first with a low and later with a high psilocybin dose. After that time, the psilocybin-treated group reached median survival, and the remaining mice were euthanized.

Psilocybin significantly improved the survival of aged mice compared to untreated mice. It also improved overall fur quality, hair growth, and reduced white hair; however, this was not quantified.

“This is a very exciting and clinically relevant finding that suggests that even when intervention is initiated late in life, it can have dramatic impacts,” said Dr. Kosuke Kato, lead author of the study and assistant professor of medicine at Baylor.

Further optimization is needed

While these results are promising, there is a need to optimize further and test the possibility of initiating the treatment earlier in life, which can possibly lead to greater effects.

“It is important to note that additional research is needed to validate these findings in human studies,” Kato said. “There is still a lot to understand, including optimal dosing protocols that will lead to maximal efficacy. We also need to better understand the potential risks of long-term psilocybin treatment before this type of treatment is ready for public use.”

Future studies also need to address the sex-specific effect of psilocybin. Some studies reported sex-specific effects of psilocybin in rodents, but the results are inconsistent and need clarification [7].

To minimize the effect of sex as a variable, in this study, the researchers studied only female mice; therefore, there is a need to test whether the described effect is also present in male mice.

What’s promising is that psilocybin seems to have minimal adverse side effects and has received FDA’s designation as a breakthrough therapy: a “process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).”

Anti-aging potential

The researchers point out that their results, for the first time, show psilocybin’s impact on multiple hallmarks of aging (cellular senescence, telomere attrition, genomic stability, and altered intracellular communication) and suggest psilocybin’s potential as an anti-aging agent and a potential therapeutic for age-related diseases.

“Our findings open an exciting new chapter in psychedelic research beyond its neurological and psychological benefits,” Hecker says. “Psilocybin may represent a disruptive agent that promotes healthy aging. The next steps need to explore the therapeutic effects across multiple age-related diseases.”

Yes I will donate❤️

Literature

[1] Kato, K., Kleinhenz, J. M., Shin, Y. J., Coarfa, C., Zarrabi, A. J., & Hecker, L. (2025). Psilocybin treatment extends cellular lifespan and improves survival of aged mice. npj aging, 11(1), 55.

[2] Raison, C. L., Sanacora, G., Woolley, J., Heinzerling, K., Dunlop, B. W., Brown, R. T., Kakar, R., Hassman, M., Trivedi, R. P., Robison, R., Gukasyan, N., Nayak, S. M., Hu, X., O’Donnell, K. C., Kelmendi, B., Sloshower, J., Penn, A. D., Bradley, E., Kelly, D. F., Mletzko, T., … Griffiths, R. R. (2023). Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA, 330(9), 843–853.

[3] Goodwin, G. M., Aaronson, S. T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J. C., Bird, C., Blom, R. E., Brennan, C., Brusch, D., Burke, L., Campbell-Coker, K., Carhart-Harris, R., Cattell, J., Daniel, A., DeBattista, C., Dunlop, B. W., Eisen, K., Feifel, D., Forbes, M., … Malievskaia, E. (2022). Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. The New England journal of medicine, 387(18), 1637–1648.

[4] Germann C. B. (2020). The Psilocybin-Telomere Hypothesis: An empirically falsifiable prediction concerning the beneficial neuropsychopharmacological effects of psilocybin on genetic aging. Medical hypotheses, 134, 109406.

[5] de la Fuente Revenga, M., Zhu, B., Guevara, C. A., Naler, L. B., Saunders, J. M., Zhou, Z., Toneatti, R., Sierra, S., Wolstenholme, J. T., Beardsley, P. M., Huntley, G. W., Lu, C., & González-Maeso, J. (2021). Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell reports, 37(3), 109836.

[6] Inserra, A., Campanale, A., Cheishvili, D., Dymov, S., Wong, A., Marcal, N., Syme, R. A., Taylor, L., De Gregorio, D., Kennedy, T. E., Szyf, M., & Gobbi, G. (2022). Modulation of DNA methylation and protein expression in the prefrontal cortex by repeated administration of D-lysergic acid diethylamide (LSD): Impact on neurotropic, neurotrophic, and neuroplasticity signaling. Progress in neuro-psychopharmacology & biological psychiatry, 119, 110594.

[7] Tylš, F., Páleníček, T., Kadeřábek, L., Lipski, M., Kubešová, A., & Horáček, J. (2016). Sex differences and serotonergic mechanisms in the behavioural effects of psilocin. Behavioural pharmacology, 27(4), 309–320.

Date Posted: July 15, 2025

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The 2025 Longevity Summit Dublin

The 2025 Longevity Summit Dublin was held in July, and we have the highlights from the event for you along with the latest research updates and news from the conference.

The Summit was founded by Aubrey de Grey and Martin O’Dea in 2022 and combines a plethora of noteworthy researchers and advocates in the rejuvenation biotechnology field.

Hosted in Dublin at the historic Trinity College, it is Ireland’s leading university, ranked No. 1 in Ireland and 87th best in the world. It was founded in 1592 and has a rich history and a reputation for excellence in education, research and innovation. Famous writers Oscar Wilde and Samuel Beckett, and scientists William Rowan Hamilton and Ernest Walton, attended Trinity College.

This makes it the ideal place to host a conference focused on the frontiers of biology, technology and human innovation. Since its inception in 2022, the Summit has cemented its place in the longevity event landscape.

Day one: Longevity goes public

The event was a four-day affair, with the first day free and open to the public and devoted to women’s health and aging. This area of research is neglected, in particular that of female reproductive aging and female aging in general. It was good to see that this was the theme of the first day.

Having the first day of the conference open to the public is a clever move. Like it or not, aging and rejuvenation research is a niche topic, and it’s not one that the public is likely going to pay to learn about. So, having a day free to attend means that curious people can whet their appetites, and it helps to spread the word.

While we are some years away from the first therapies reaching the healthcare system, there are quite a few rejuvenation therapies in clinical trials right now. Mass public awareness and support is unlikely until these therapies begin to arrive. At that moment, the acceptance that aging decline is something we can address is likely to become widespread.

Day two: Longevity talks begin

The second day saw the start of scientific talks that were targeted at researchers and people who are invested in the field. There was a mix of speakers this year, and some of the talks were particularly impactful.

Healthspan and lifespan are mutual goals

Martin O’Dea welcomed guests with his opening talk. Martin is a well-known figure in the longevity community, an experienced businessman, an author, and the CEO of Longevity Events Limited, which hosted the Longevity Summit Dublin.

He reflected on the recent trend of longevity and how the conference was trying to combine public interest in healthspan and well-being with the actual science of rejuvenation. He also cautioned that while he believed the two things could work together, it was important to ensure that science remained the focus for the event.

Martin suggested that lifespan and healthspan aren’t in opposition but that they need to be combined to work together and not in opposition. He said, “We can chew gum and walk; we can do healthspan and lifespan together.”

The idea that lifespan and healthspan are separate and competing goals makes little sense when you think about the actual biology at play here. It is not impossible to increase one but not the other, the modern healthcare system has achieved this by increasing lifespans but not healthspans, but the two are strongly linked.

The goal of our field is not to increase one over the other. The aim is to provide both longer and healthier lifespans for everyone. Ultimately, this is about quality and quantity, and this is what Martin was driving at in his opening talk.

Nanotics could really shake up rejuvenation biotechnology

The first presentation was by Lou Hawthorne from biotech company NaNotics, which pushes the envelope in trying new things. Its approach is to use NaNots to remove target molecules from blood without the use of drugs or external filtering devices.

NaNots are tiny artificial structures that lock in the target molecules away, making them ready to be excreted by the body. One advantage of NaNots is that they can remain in blood for days while absorbing these molecules.

This company’s current focus is on tumor necrosis factor (TNF), a regulator of the immune system and inflammatory response. NaNots only target the soluble TNF in blood and ignore membrane TNF, which is important as the membrane-bound form of TNF is very important for healthy cell function. NaNots are able to be selective in this manner, unlike traditional drugs that can target both forms.

Lou mentioned that the soluble form of TNF is linked to multiple sclerosis (MS) and that the company is hoping to move to the clinic to try to cure it. He reported that the mouse data they have for the approach is promising enough to move towards a clinical trial.

NaNots may also potentially be applied to deal with cancer metastases and tumors. Lou said that the company is also looking at PDL-1 with cancer treatment in mind. Additionally, the company intends to tackle sepsis and the resulting cytokine storm it causes, and in addition to TNF, it hopes to use NaNots to hoover up soluble interleukin-1β and interleukin-6 cytokines.

More generally, inhibiting unwanted pro-inflammatory cytokines could potentially be used to address inflammaging, the smoldering background of inflammation present in the majority of older people. NaNotics plans to use its product to target these inflammatory signals, which are secreted by senescent cells and created by other sources. Effectively, NaNots might be used as a form of senotherapeutic.

If the chronic inflammation observed in older people could be effectively reduced without harming healthy cell function, it might delay or even prevent a number of age-related diseases. NaNots are a new and highly selective approach to old problems.

Life Biosciences is bringing partial cellular reprogramming to the clinic

Michael Ringel from Life Biosciences had some interesting news about his company’s work on Yamanaka factors.

The expression of the Yamanaka factors Oct4, Sox2, Klf4, and c-Myc (OSKM) has been found to restore youthful gene expression patterns, reverse epigenetic age, and make old cells and tissues functionally younger.

Life Biosciences has been exploring these so-called reprogramming factors for a number of years, hoping to reverse epigenetic alterations, one of the reasons we age.

It is known that exposing old cells to these factors can make them functionally young again; however, doing so reverts their types to a developmental state. This is a problem because we don’t want the target cells to have their identities erased; heart cells forgetting they are heart cells would be a big problem!

Fortunately, researchers worked out that if cells are only exposed to the Yamanaka factors for just a brief period of time, it is enough to reverse their age without erasing their identities. This is known as partial cellular reprogramming.

The tricky thing is achieving this transient exposure in living animals. Life Biosciences has worked out a way of achieving this short-term exposure.

The company has been using just three of these factors in its research: Oct4, Sox2, and Klf4 (OSK). There was a concern that c-Myc could encourage the onset of cancer, and, as fortune would have it, not using it still allowed partial reprogramming to occur.

Michael explained that the company is now focusing its efforts on bringing partial cellular reprogramming to the clinic later this year. It is planning to move to Phase 1 for optic neuropathy, particularly glaucoma and non-arteritic anterior ischemic optic neuropathy (NAION).

The company is using doxycycline, something not found in nature, to turn on OSK gene copies delivered to target cells. This allows them to transiently turn the OSK genes on or off based on the presence of doxycycline. Effectively, this acts as a kill switch if things go wrong and controls exposure just enough to partially reprogram the old cells back to being young.

Life Biosciences has demonstrated that this works in mice with age-related optical neuropathy and reports that primate study results have been positive. It seems that partial cellular reprogramming is finally approaching the clinic after decades of research. If successful, it could offer a potential solution to repairing and rejuvenating aged cells and tissues.

Positive results for therapeutic plasma exchange in human trials

Dobri Kiprov from Global Apheresis was on hand to talk about the latest results from his research in therapeutic plasma exchange (TPE). He discussed how his results support that the rejuvenation effect seen in TPE is due to a dilution effect on the negative factors in aged blood, rather than there being some secret sauce in young blood.

He went on to explain that fresh albumin is anti-inflammatory and that replacing the old albumin improves patient outcomes. So far, his company has conducted two human trials for Alzheimer’s using TPE, with the results suggesting the procedure is safe.

The second, larger trial involved 40 people and included sham apheresis. Patients were either hooked up to an apheresis machine to have albumin exchanged or connected to a noise-making machine behind a curtain that did not actually exchange plasma. In this way, the participants had no idea if they were receiving actual TPE or just a mock treatment. This second trial also had two treatment frequencies in the test group.

Dobri reported that grip strength and balance improved in all treatment groups but not in the sham one. This trial used an impressive 35 aging clocks, and, broadly speaking, there was a significant reversal of aging markers. It seems that TPE rejuvenates the stem cell niche and makes the signaling environment more like that seen in younger people.

The take-home here is that the effects of TPE, as demonstrated in mouse studies by people such as Irina and Michael Conboy, appear to translate to humans. This means that TPE could potentially help us to stay healthier and biologically younger for longer.

However, for a rejuvenation technology to be truly successful, it needs to be both cost effective and scalable. As TPE likely needs to be done 3-4 times a year, based on what Dobri suggested, there must be a lot of procedures conducted. As many people would likely want TPE for its anti-aging effects, there is a question of scalability. Clearly, that is a consideration that will require creative solutions.

Perhaps even more intriguing is the possibility we could find out exactly what it is about aged plasma that is harmful and repair it in situ, instead of replacing it with new albumin. NaNots and other new technologies might be harnessed to that effect to achieve this, depending on what needs fixing in the albumin of course. One thing is certain, now we know that TPE works for people, the race is on to find scalable solutions.

A new early type of stem cell

Yuta Lee from Accelerated Biosciences announced that his company has the earliest form of stem cell free from ethical issues. Human trophoblast stem cell (HTSC) stem cells are gathered from ectopic pregnancies, which occur when a fertilized egg implants itself outside of the womb, usually in one of the fallopian tubes.

These stem cells are the earliest stem cells without ethical concerns, as the embryo is non-viable in these pregnancies. They are between embryonic stem cells and mesenchymal stem cells in terms of lineage and potency. Yuta suggested that these HTSC stem cells are also apparently clean of endogenous viruses.

One of the advantages of HTSCs is they are highly scalable due to the number of potential cell passages compared to other types of stem cells.

Yuta reported that HTSC cell secretions, like those of other types of stem cells, inhibit the inflammatory SASP secreted by senescent cells. That suggests that they may find application in the treatment of inflammatory diseases and conditions.

The company has already been successful in its good manufacturing practice (GMP) requirements. GMP describes the minimum standard that a medical manufacturer must meet in their production processes. Accelerated Biosciences wants to work with others to bring solutions for age related diseases.

Cyclarity Therapeutics progressing with human clinical trials

Earlier this year, we interviewed Matthew (Oki) O’Connor after Cyclarity launched human trials to Cure atherosclerosis, and he was at the Summit with an update.

The good news is that the initial part of Cyclarity’s Phase 1 clinical trial in Adelaide is done. The first five dosing levels are complete, and no adverse reactions have been observed with UDP-003.

The next step is about to begin; this will be the ascending dose group. The purpose of this is to gain an initial insight into the pharmacokinetics of a drug’s single dose and its safe dosage range. It is recommended to administer doses to participants one after another, allowing sufficient observation time between each.

Oki also mentioned that Cyclarity is planning for a 150-person trial for Phase 2 in Europe. While there is no date on that yet, they are pushing hard on Phase 1 and so it could even be this year.

Finally, he revealed that his company is developing an AI-based system to optimize cyclodextrin drug development. While the plaques in atherosclerosis are the target of UDP-003, Cyclarity is interested in removing other harmful molecules using this system.

Cyclarity is also working on finding solutions to nanoplastics, things like BPA and PFAS that the company believes its technology could potentially address. This could potentially address unhealthy levels of nanoplastics in people and remove them from the blood, cells, and tissues where they have accumulated.

We are looking forward to hearing more from Cyclarity and are proud that we helped this company to be founded. Heart disease is the number one killer worldwide; to have a solution to treat it effectively would be game-changing.

Our knowledge of female biology and aging is lacking

Jennifer Garrison from the Buck Institute waded in on female biology and aging. She believes that a loss of homeostasis systems in the brain regulates aging. Jennifer highlighted that male biology is better understood than female biology.

She said that females have a shorter healthspan than males. Some of this is likely due to how fast ovaries age, up to twice as fast as other organs. Ovaries appear to be part of a wider signaling system, which isn’t well understood but appears to promote female healthspan and lifespan.

Jennifer talked about how perimenopause causes a breakdown of this communication and promotes aging, and menopause does even more of this.

She said that HRT is a band-aid and can reduce all-cause mortality by up to 30% if given within ten years of menopause. Also, on average, if menopause is later in life, then lifespan is often longer as well. She believes that if we can extend ovarian function by delaying aging of the organ, we could increase female healthspan.

More funding for female aging is urgently needed. Women’s health is seeing research cutbacks by the NIH at a time when it badly needs to be improved. It is more important than ever that more focus is put into understanding how women age and the additional functions ovaries play in that aging.

There are now a number of companies exploring female aging. If their efforts to rejuvenate or extend the healthspan of ovaries succeeds, this will be a great demonstration that aging is not a one-way street.

Lifespan Research Institute: A new org, a new direction

Lifespan Research Institute (LRI) President Keith Comito focused on the always-important need to work together to face the challenges our field presents. Solving aging is the greatest challenge humanity has ever faced, and, as a relatively young industry, it is critical that we collaborate where possible to make rapid progress.

Among the challenges we face is getting wide public support for rejuvenation biotechnology. Keith said, “Bringing the public along with us on the journey is important. We need to meet them where they are, rather than assume they will just get on board.”

Regarding public engagement, he ventured that developing AI-based tools could also help support effective advocacy and determine public sentiment towards rejuvenation biotechnologies. Keith is well known for his work with AI and other disruptive technologies and he feels they could be used to great effect for our field.

He gave four historical examples where interest in rejuvenation appeared to peak:

Imagine if we had AI-based tools to help interpret these peaks in public interest and to help identify what approaches work best. This would mean we could more effectively engage with people about the field. We will have more to say about new public advocacy tools in the near future.

Keith also highlighted the importance of non-invasive biomarkers of aging and how machine learning might be a useful tool in our longevity arsenal. He gave an example of when machine learning was used as a detection method for COVID-19.

He suggests that machine learning and AI more generally may be adapted in the context of aging research. For instance, it isn’t hard to imagine how an AI based biomarker system may be useful in the context of functional aging.

Consider a system that could examine gait and body movement and identify trends associated with age-related changes. Combined with clinical biomarkers, these non-invasive biomarkers could potentially help round out more comprehensive biomarker panels.

Finally, Keith took the opportunity to talk about the LRI, our new organization created by the merger of LEAF and SENS in October last year. We have launched a new website that showcases our work and explains how we are adapting to the changing landscape of longevity and rejuvenation research.

LRI has five broad guiding principles behind its research.

Ability To Boldly Impact the Biology of Aging and Extend Healthy Life
Capability for Rapid Translation into Humans
Uniqueness and Non-Duplicative Effort
Paradigm-Shifting Technological Advances
Ability to Inspire the Public and Lead the World to Prioritize Aging Research

At our Mountain View, California research center, we have two pioneering labs working on repair-based solutions to age-related diseases.

The Boominathan Lab: Dr. Amutha Boominathan’s research team focuses on exploring mitochondrial biology, creating gene therapies to treat mitochondrial issues, and improving therapies for conditions associated with mitochondrial DNA mutations and aging processes.

The Sharma Lab: Dr. Amit Sharma’s research team is exploring the impact of aging and cellular senescence on immunity with a focus on creating approaches to utilize immune responses for identifying and eliminating senescent cells.

The emphasis is very much on actionable research that helps propel the field forward as rapidly as possible. If you would like to support our non-profit mission for longer and healthier lives, see how you can help us.

See you next year for more longevity and rejuvenation

There were many more talks during the conference, too many to list and discuss here. We have picked out the ones that most resonated with us and our mission of accelerating technologies to overcome age-related disease and extend healthy human lifespan.

The Lifespan team was delighted to be a part of this year’s conference, and we would like to thank our hosts for inviting us. We are looking forward to the 2026 Longevity Summit in Dublin and wish Martin and the team the best in making that happen!

Date Posted: July 15, 2025

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Non-Toxic Stem Cell Transplantation Prevents Cancer in Mice

Scientists have developed a protocol for hematopoietic stem cell transplantation that reconstructs a healthy blood system and prevents blood cancers in old mice while also reducing toxicity [1].

The blood factory

Hematopoietic stem cells (HSCs) work hard for our entire lives, producing vast numbers of various blood cells. As we age, this process, like many others in the body, gets dysregulated [2]. This contributes to the decline of the immune system and to the development of several harmful conditions, including blood cancers.

HSC transplantation is a feasible strategy, but it requires depleting the host’s own stem cells to make space in the bone marrow niche for the donor’s cells to engraft. Today, this is achieved mostly by chemo- and radiotherapies, which are notorious for their powerful side effects [3]. In a new study published in Nature Communications, researchers at the Lund Stem Cell Center at Lund University, Sweden, attempted to develop a safe and effective method for transplanting young, healthy HSCs into aged recipients.

“Conventional transplantation requires patients to undergo chemotherapy or irradiation to eliminate malignant cells, suppress immune rejection, and make room for new stem cells in the bone marrow,” explained David Bryder, Professor of Molecular Hematology at Lund University. “But these treatments are highly toxic, especially for older individuals, who are also the ones most likely to benefit.”

More cells, more drugs, less toxicity

First, the researchers tested an existing non-genotoxic conditioning agent, CD45-saporin (CD45-SAP), an immunotoxin that selectively eliminates HSCs without widespread toxicity, in both young (2-month-old) and aged (16-month-old) mice. Then, the team transplanted young HSCs and monitored the success of the transplant.

The team found that the conditioning was much less effective in aged mice. While CD45-SAP successfully depleted HSCs in young mice, a significant number of the host’s own HSCs remained in the aged mice. Consequently, when young HSCs were transplanted, they engrafted successfully and created new blood cells in the young mice but not in the aged group.

Having found that standard doses of HSCs fail to engraft well in aged mice, the researchers explored whether using a much larger number of donor HSCs could force a successful transplant. They expanded a small number of young HSCs into a large population ex vivo and then transplanted these cells into young mice, hypothesizing that the available niches for HSCs in the bone marrow might be more reliably populated if “flooded” with sufficient numbers of donor cells.

At this stage, the researchers used only young mice to prove that an increase in HSC numbers can improve transplantation outcomes. Transplanting large numbers of expanded HSCs indeed led to successful, long-term multilineage blood cell production even in unconditioned young hosts. Combined with CD45-SAP conditioning in young mice, the result was a robust and near-complete reconstitution of the blood system.

“In particular, the mice showed a strong resurgence in the production of naïve B and T lymphocytes, cells that play a key role in immune defense, which usually decline with age,” said Bryder. “These young cells didn’t just survive; they reshaped the entire immune landscape. We were especially encouraged to see that the new cells maintained long-term function and diversity, even within an aged environment.”

The researchers hypothesized that the primary problem with aged hosts was the failure to clear out enough of the old, resident HSCs. To fix this, they developed a more potent conditioning regimen by adding to the CD45-SAP immunotoxin a two-drug mobilization regimen (G-CSF/AMD3100), which forces the remaining host HSCs out of their protective bone marrow niches and into the bloodstream.

“Instead of using conventional chemotherapy, we deployed antibody-toxin conjugates, also known as immunotoxins, that selectively target and deplete the recipient’s own HSCs while sparing surrounding tissues,” explained Anna Konturek-Ciesla, postdoctoral researcher and first author of the study. “This was paired with a drug-based mobilization strategy that temporarily displaces stem cells from the bone marrow, creating space for incoming donor cells.”

Successful prevention in vivo

Finally, the researchers tested their strategy in a disease context, using a transgenic mouse model (NHD13) that is genetically predisposed to developing myelodysplastic syndrome (MDS) and acute leukemia, common blood disorders in elderly humans. They treated two-month-old mice with the combined conditioning regimen and transplanted healthy, wild-type bone marrow cells. The mice were then monitored for their entire lifespan.

In the untreated group, 75% of the mice developed blood malignancies, versus just 33% in the study group. Most strikingly, while 25% of untreated mice developed aggressive acute leukemia, none of the transplanted mice did.

The treatment was initiated at this young age because these transgenic mice develop symptoms early. The researchers also position their invention as “a prophylactic tool to delay or even prevent” the onset of age-associated hematological disorders. Potentially, non-toxic HSC transplantation can be used in an even wider context in order to prevent age-related immunosenescence, which is considered a major cause of aging and mortality.

“While these findings are currently limited to animal models, and there are many more steps to take before this can be applied in humans, they offer a proof-of-concept, that aged or malfunctioning stem cells can be safely replaced (without the toxicity of traditional conditioning) and that youthful blood production can be restored even in an older body,” summarized Konturek-Ciesla.

Literature

[1] Konturek-Ciesla, A., Zhang, Q., Kharazi, S., & Bryder, D. (2025). A non-genotoxic stem cell therapy boosts lymphopoiesis and averts age-related blood diseases in mice. Nature Communications, 16(1), 5129.

[2] Kim, M. J., Kim, M. H., Kim, S. A., & Chang, J. S. (2008). Age-related deterioration of hematopoietic stem cells. International journal of stem cells, 1(1), 55-63.

[3] Gyurkocza, B., & Sandmaier, B. M. (2014). Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood, The Journal of the American Society of Hematology, 124(3), 344-353.

Date Posted: July 14, 2025

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How Blood-Brain Barrier Leaks Make Parkinson’s Worse

Researchers have discovered how α-synuclein (α-syn), a key protein in Parkinson’s disease and Lewy body dementia, leads to inflammation and disruption of the axons in the brain.

Failure of the barrier

Unlike other organs, the brain is heavily protected from many compounds in the bloodstream in order to prevent damage, with a unique combination of cells and junction proteins involved in this layered defense: this is the blood-brain barrier (BBB) [1]. As expected, damage to the BBB is directly related to neurodegenerative diseases [2].

This relationship has been very heavily studied for Alzheimer’s disease [3], but only limited work has been done to tie together the BBB and α-synucleinopathies [4]. While most work on α-syn has focused on how it directly damages cells in the context of Parkinson’s [5], these researchers note that BBB damage is likely to have its own negative effects that need to be included for accurate drug development [6].

Aggregates cause damage to cells

For accurate results, the researchers investigated both the usual, monomeric form of α-syn along with an aggregate called preformed fibril α-syn (PFF). They then introduced each of these proteins to endothelial cells that line the BBB (HBMVECs) in vitro.

Both regular α-syn and PFF were taken up by the HBMVECs. While these cells did not react to the aggregate within the first hour, the PFF fibrils were carried to lysosomes for processing within a day. Before it could be properly processed, however, PFF was found to lead to disruption of vascular endothelial cahedrin (VE-cadherin), a core protein of the BBB. This disruption led to increased penetration of a form of dextran thaat does not normally penetrate the BBB. Unaggregated α-syn, which is associated with normal function, did not have such effects.

A gene expression analysis revealed a link to inflammation. While there were no interesting differences between the monomeric α-syn group and the control group, the PFF group had significant differences. At 24 hours, a gene cluster that is related to inflammatory factors, such as NF-κB and TNF-α, was strongly upregulated compared to controls. Cellular proliferation and growth were also impeded according to this analysis.

Because genes are strongly inter-related and the underlying biology is exceptionally complicated, the researchers used an AI algorithm to determine what upstream pathways were responsible for this change in gene expression; many of these genes were well-known in the literature for being related to inflammation. They also found that TNF-α was uniquely upregulated, becoming elevated by nearly 250-fold within one hour compared to controls.

Critically, inhibiting TNF-α in these cells, while it did not completely reverse the effects, led to lower permeability of dextran. This suggests potential benefits for the BBB.

Heavy BBB leakage in mice

The researchers used mice that were modified to aggregate α-syn (G2-3 mice), first confirming that these aggregates were indeed found in both the brain tissue and in the vasculature. They then tested for claudin 5, a core protein responsible for BBB integrity. Unsurprisingly, they found that claudin 5 in G2-3 mice was significantly decreased from that of wild-type mice, although it took 13 months of aging for this damage to appear to a statisticallly significant degree. An antibody for immunoglobulin G (IgG) demonstrated a tremendous amount of BBB leakage: at 13 months, approximately six times as much IgG had worked its way into the brains of the G2-3 mice than those of wild-type mice.

Pericytes, along with the endfeet of astrocytes, are also part of BBB maintenance. Compared to wild-type controls, the G2-3 mice had more astrocytic activity, showing that they were working harder to compensate for the porous BBB. However, aquaporin 4, a protein involved in disposing of potentially dangerous waste, was depleted, which suggests that the astrocytes were overwhelmed. Similarly, a marker of pericyte activity, PDGFRβ, was upregulated, suggesting that these cells were also working much harder to defend the leaky BBB.

Small vessel disease (SVD) is a BBB failure that leads to nerve damage. Microglial inflammation near the vasculature, which is found in SVD, was also found in the G2-3 mice. Degeneration of the extracellular matrix was discovered, and there was evidence of axonal damage near the vasculature as well.

A potential treatment may already exist

In another experiment, the researchers used a wild-type strain of mice and injected their brains with PFF. They then dosed some of the mice with etanercept, a TNF-α inhibitor that is used to treat arthritis and does not normally penetrate the BBB. Compared to the mice that received PFF but not etanercept, the treated mice had significantly less IgG infiltration, nearly to the levels of the control group. Very significant effects were also found when etanercept was given to G2-3 mice, including benefits against the effects of SVD.

Etanercept was also found to have downstream benefits in mice. α-syn aggregation was found to cause damage to both novel object recognition, which measures cognitive function, and the rotarod test, which measures balance ability. Both of these metrics were improved with etanercept.

While there is still no evidence that this could work as a treatment for Parkinson’s in human beings, it is clear that BBB disruption and the resulting inflammation are likely to strongly contribute to Parkinson’s pathology. A clinical trial could validate whether etanercept or another drug that disrupts TNF-α could blunt the effects of this debilitating disease.

Yes I will donate❤️

Literature

[1] Jeon, M. T., Kim, K. S., Kim, E. S., Lee, S., Kim, J., Hoe, H. S., & Kim, D. G. (2021). Emerging pathogenic role of peripheral blood factors following BBB disruption in neurodegenerative disease. Ageing research reviews, 68, 101333.

[2] Baloyannis, S. J., & Baloyannis, I. S. (2012). The vascular factor in Alzheimer’s disease: a study in Golgi technique and electron microscopy. Journal of the neurological sciences, 322(1-2), 117-121.

[3] Ryu, J. K., & McLarnon, J. G. (2009). A leaky blood–brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain. Journal of cellular and molecular medicine, 13(9a), 2911-2925.

[4] Pediaditakis, I., Kodella, K. R., Manatakis, D. V., Le, C. Y., Hinojosa, C. D., Tien-Street, W., … & Karalis, K. (2021). Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption. Nature communications, 12(1), 5907.

[5] Michel, P. P., Hirsch, E. C., & Hunot, S. (2016). Understanding dopaminergic cell death pathways in Parkinson disease. Neuron, 90(4), 675-691.

[6] Elabi, O., Gaceb, A., Carlsson, R., Padel, T., Soylu-Kucharz, R., Cortijo, I., … & Paul, G. (2021). Human α-synuclein overexpression in a mouse model of Parkinson’s disease leads to vascular pathology, blood brain barrier leakage and pericyte activation. Scientific reports, 11(1), 1120.

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The blood factory

More cells, more drugs, less toxicity

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Literature

Failure of the barrier

Aggregates cause damage to cells

Heavy BBB leakage in mice