Study Paves Road for Oral Delivery of Proteins

Date Posted: August 5, 2025

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Study Paves Road for Oral Delivery of Proteins

Using a pathogen-originated protein and a human antibody, scientists have created a chimeric construct that can deliver protein cargo via the intestine. This technology could potentially replace cumbersome injections [1].

Getting rid of the needle

Protein-based treatments are very powerful, but they cannot yet be administered orally because the human gut breaks proteins down. Instead, such treatments, which include antibodies, certain hormones, and peptides, are administered as injections, which are much more cumbersome to deliver. A new study from the University of Bath, published in the Journal of Controlled Release, offers an ingenious potential solution.

The researchers used the ability of cholix (Chx), a toxin produced by Vibrio cholerae, the bacteria that causes cholera, to penetrate gut cells. They trimmed Chx down to its first 197 amino acids, rendering it benign while preserving its cell-penetrating ability, and linked it to human growth hormone (hGH), which is used to treat certain disorders and is being researched in the context of longevity, with mixed results [2].

To make hGH enter the bloodstream, it must be eventually detached from the Chx domain. The protease (protein-cleaving enzyme) furin can do it, so furin-cleavable sequences were introduced to the chimera. Furin is abundant in enterocytes, the absorptive cells that form the lining of the small-intestinal villi and take up nutrients. The idea was that if the chimera could travel across the entire cell to its basal region, and get cleaved by furin there, hGH would be released into the bloodstream.

Using antibodies did the trick

However, the Chx-hGH chimeras were instead cleaved by furin soon upon arrival in enterocytes, crashing bioavailability. To overcome this challenge, the researchers turned to human IgG1 antibodies, adding one of their domains, CH2, to the chimera.

When grafted onto other proteins, CH2 can sometimes act as an address tag that can direct the chimera towards a certain route inside the cell [3]. The researchers found that CH2-incorporating chimeras less often ended up being cleaved by furin at the apical end of the cell, which faces the intestinal wall. Instead, they seemed to be rerouted and successfully transported across the cell, arriving at the basal end, which faces the bloodstream, and being cleaved by furin there.

The researchers also noticed that these improved chimeras were colocalized with the protein FCRLA. It might be that, with CH2 as a ‘swipe-badge’, the chimera was allowed into FCRLA-marked back corridors, keeping the linker intact for longer. However, the researchers still do not understand the mechanism behind this effect.

With the help of this bag of tricks, the team’s best-performing chimera delivered roughly 4% of the dose into the rats’ bloodstream without any noticeable toxicity. According to the paper, this is among the highest reported in pre-clinical protein studies and more than enough to start thinking about translation into actual treatments.

“This pathway is well understood and has been derived from events in the human intestine, so we know it will work in patients,” said Professor Randy Mrsny, from the University of Bath’s Department of Life Sciences, who led the study. “Unlike previous systems, our method doesn’t damage the epithelium and can generically transport a large range of medications, including hormones and cancer treatments that can currently only be injected. This has the potential to transform the lives of patients who currently have to inject themselves daily, such as children who need to take growth hormones.”

Not exactly the oral route, for now

However, there are a few caveats. First, the delivery in the rat model was performed not orally but by a direct injection into various parts of the intestine while isolating them by clamping the rest of the gut. The researchers found that absorption in the ileum, the final section of the small intestine, was much greater than in the other parts. Compared to this “idealized” method of delivery, the conventional oral route poses significant challenges and would require a lot of tuning.

Second, no antibody-formation or immune-activation studies were performed. The authors do not discuss whether repeated exposure to a bacterial-protein carrier or the human CH2 tag might trigger neutralizing antibodies or hypersensitivity. In summary, the acute rat model that the team used cannot reveal longer-term issues such as receptor saturation in the ileum, effects on gut barrier integrity, or unintended delivery of cargo to immune cells.

The researchers, however, are quite optimistic. “While it’s not the first system to replace injections, ours is the first platform to work safely and consistently, delivering the drug at effective doses and using a well-understood pathway,” said Mrsny. “Once it’s been developed into a pill, our system would be more convenient for patients than injections, meaning no more needles.”

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Literature

[1] Taverner, A., Hunter, T., MacKay, J., Varenko, V., Gridley, K., & Mrsny, R. J. (2025). Human Fc CH2 domain modifies cholix transcytosis pathway to facilitate efficient oral therapeutic protein delivery. Journal of Controlled Release, 113964.

[2] Fernández-Garza, L. E., Guillen-Silva, F., Sotelo-Ibarra, M. A., Domínguez-Mendoza, A. E., Barrera-Barrera, S. A., & Barrera-Saldaña, H. A. (2025). Growth hormone and aging: a clinical review. Frontiers in Aging, 6, 1549453.

[3] Ying, T., Wang, Y., Feng, Y., Prabakaran, P., Gong, R., Wang, L., … & Dimitrov, D. S. (2015, September). Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn. In MAbs (Vol. 7, No. 5, pp. 922-930). Taylor & Francis.

Date Posted: August 4, 2025

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A Brain Clock for Finding Rejuvenating Medications

Researchers have developed a transcription-based clock that estimates brain age and used it to identify potential interventions against age-related neurodegeneration.

Deciding which -omic to use

While neurodegeneration and brain aging are not precisely the same [1], the two are tightly linked [2]. Substantial previous work has found that directly addressing brain aging in multiple forms, including the use of Yamanaka factors to facilitate epigenetic rejuvenation, leads to better outcomes in models [3]. However, finding the right approaches, particularly approaches that can be safely and effectively administered to human beings, has proven difficult.

These researchers note the distinctions between transcriptomic and proteomic approaches, which measure RNA and protein expression in a cell, to epigenetic approaches that measure DNA methylation. While they acknowledge that epigenetics are more stable and better for estimating age, this transcriptomic clock’s focus is on identifying changes in cellular function, which are directly altered by interventions and are far easier to interpret. Previously, this team created a similar clock for skin [4], but this is their first foray into creating something for the brain.

Large datasets for an accurate clock

To generate their clock, the researchers used bulk data from multiple major datasets, including an Alzheimer’s-related database, a tissue expression project, a study on traumatic brain injury and dementia, and a brain-specific gene expression study. In total, there were 778 unique people (all healthy, age range 20 to 97), 2,458 samples, and 43,840 transcriptional profiles of both neuronal progenitor cells (NPCs) and neurons. With this data, this team created a clock that uses the transcriptions of 365 genes to judge how well interventions might impact the brain.

Despite not being an epigenetic clock, it was found to be highly accurate for estimating chronological age. While their test set yielded an average error of 2.55 years, an external validation set found the average deviation to be approximately 6 years. Despite being based on bulk sequencing data, it was still found to be predictive of age when used on data derived from single-cell sequencing.

Of the 365 genes, 91 were found to be specific to brain processes. Synapse functionality was a common finding, but the strongest connection between aging and transcriptomics was found to be related to the development of the helper cells known as microglia. DNA processing was very commonly associated as well, and sterol metabolism was also noted. Interestingly, genes that had been specifically marked as relating to neuropathology had less representation than the researchers had expected.

There was, however, a significant link between neuropathology and transcriptomic brain aging. The researchers derived other samples from unhealthy donors and found that people with neurodegenerative disorders, such as Alzheimer’s and Parkinson’s, had older brains according to this clock, with extremely small p-values. There was also a highly significant correlation between disease severity and transcriptional age; people with more severe symptoms were likely to have even older brains.

Beneficial perturbations

These researchers then used both chemical and genetic perturbation datasets to identify how they impacted the transcriptome of their clock, finding 4,047 perturbations that affect neurons and 5,770 that affect NPCs. Of course, it is easier to cause accelerated aging than to rejuvenate, but the researchers found 971 perturbations that led to their clock signaling rejuvenation in NPCs and 68 in neurons.

Two of the strongest transcriptomic rejuvenators in NPCs were found to be BGT-226 and WYE-354, which inhibit mTOR and were tried but not approved as cancer drugs. Both of them have a similar mechanism of action as rapamycin and related drugs. Other rejuvenators include alvocivid, an approved leukemia drug; iloprost, an approved hypertension drug that has never been investigated for age-related benefits; and an entirely experimental compound, BRD-K48950795. In neurons, a variety of potential cancer drugs along with the approved cancer drug ponatinib were found to be rejuvenators.

Some of the beneficial perturbations were found to be directly related to known hallmarks of aging. For example, anti-inflammatory compounds were predicted to reduce transcriptomic age, and a compound that inhibits hypermethylation and thus slows epigenetic aging was also noted. A total of 23 of the identified compounds were found to extend lifespan in animal models of aging, and many of them were chemically similar to rapamycin.

Effects in mice

The researchers then selected a potentially therapeutic combination of three of these compounds: 5-azacytidine, a rejuvenating drug according to the DrugAge database; tranylcypromine, which is similar to rapamycin; and JNK-IN-5A, which influences epigenetics. Administering this combination to 18-month-old mice appeared to reduce their anxiety in an open field test, and there appeared to be a trend towards exploring a novel object.

This combination caused more profound changes at the transcriptomic level. Mice given this combination had gene expression that was more similar to that of younger animals, suggesting functional rejuvenation.

However, this combination has not been evaluated for human use, and it is unclear if stronger combinations can be found using this clock or other transcriptomic clocks. A more in-depth examination will have to be done to determine if this line of inquiry will result in the discovery of new drugs or the repurposing of existing ones to slow or reverse some aspects of brain aging.

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Literature

[1] Nelson, P. T., Head, E., Schmitt, F. A., Davis, P. R., Neltner, J. H., Jicha, G. A., … & Scheff, S. W. (2011). Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies. Acta neuropathologica, 121(5), 571-587.

[2] Podtelezhnikov, A. A., Tanis, K. Q., Nebozhyn, M., Ray, W. J., Stone, D. J., & Loboda, A. P. (2011). Molecular insights into the pathogenesis of Alzheimer’s disease and its relationship to normal aging. PloS one, 6(12), e29610.

[3] Shen, Y. R., Zaballa, S., Bech, X., Sancho-Balsells, A., Rodríguez-Navarro, I., Cifuentes-Díaz, C., … & Del Toro, D. (2024). Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming. Cell Stem Cell, 31(12), 1741-1759.

[4] Plesa, A. M., Jung, S., Wang, H. H., Omar, F., Shadpour, M., Buentello, D. C., … & Church, G. M. (2023). Transcriptomic reprogramming screen identifies SRSF1 as rejuvenation factor. bioRxiv, 2023-11.

Date Posted: August 1, 2025

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Study Finds Metformin’s Action Is Regulated by the Brain

A new study has shown that, unlike many other glucose-lowering drugs, metformin is regulated by the protein Ras1 in a specific subset of neurons, and when injected into the brain, even tiny doses of metformin can do the job [1].

The brain connection

The safe and cheap anti-diabetes drug metformin has been in use for decades. In addition to its strong glucose-lowering activity, metformin also exerts metabolic effects that lead to weight loss, improved lipid profile, and enhanced insulin sensitivity [2].

Metformin is although one of the most famous small molecules in the longevity field. It has demonstrated healthspan benefits and, in some experiments, lifespan extension, in animal models, and it has been linked to improved health outcomes and survival in diabetic humans [3].

Despite metformin being around for so long, scientists were still not entirely sure what its mechanism of action is. It was thought that it works via peripheral organs, such as the liver and the gut. However, in this new study from the Baylor College of Medicine, published in Science Advances, researchers have found that metformin’s activity might be mediated by the brain. “The brain is now widely recognized as a key regulator of whole-body glucose metabolism and a potential therapeutic target for the treatment of diabetes,” the paper says. “However, whether and how the brain contributes to the antidiabetic effects of metformin have not been thoroughly explored.”

In one of their previous studies, the same team found that Ras-related protein 1 (Rap1) in the hypothalamus is a major regulator of whole-body glucose metabolism, and that activating it produces a diabetes-like phenotype in mice, while reducing its activity ameliorates hyperglycemia (high blood sugar) [4]. This time, the researchers set off to find whether Rap1 might regulate the effects of metformin.

The metformin-specific protein

The team genetically engineered brain-specific Rap1-deficient mice. These mice and their wild-type littermates that were used as controls received a high-fat diet (HFD) to recreate a diabetes-like condition. The animals were then treated with several glucose-lowering drugs, including metformin, sulfonylurea (glibenclamide), a GLP-1 receptor agonist (exendin-4), an SGLT-2 inhibitor (dapagliflozin), and insulin.

Interestingly, only metformin failed to significantly lower blood glucose levels in Rap1-deficient mice, while the other drugs worked as intended, suggesting that Rap1 affects some metformin-specific pathway. Circulating levels of metformin were similar in Rap1-deficient and control mice, but in the former, metformin failed to improve glucose tolerance. The researchers had to ramp up the dose of metformin considerably for it to start working in Rap1-deficient mice.

“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver. Other studies have found that it acts through the gut,” said corresponding author Dr. Makoto Fukuda, associate professor at Baylor. “We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism. We investigated whether and how the brain contributes to the anti-diabetic effects of metformin.”

Aim for the brain!

The researchers reasoned that if the brain regulates metformin’s effects, a direct injection of a small dose of the drug into the brain would exert a meaningful effect. Indeed, they found that tiny doses of metformin, which would have made no difference when administered systemically, recreated the known effects of the drug when injected intracerebroventricularly (into the fluid-filled spaces of the brain). Metformin injection also inhibited the activity of Rap1 protein in the hypothalamus.

The team created a new line of mice that expressed in their forebrain neurons a permanently active version of Rap1 that cannot be inhibited by metformin. As they predicted, these mice were resistant to metformin. The drug failed to improve their glucose tolerance, confirming that metformin’s ability to inhibit Rap1 is essential for its action.

Using advanced methods, the researchers found that metformin specifically activated a group of neurons (SF1 neurons) in a small part of the hypothalamus called the ventromedial hypothalamic nucleus (VMH). Metformin’s ability to excite these specific neurons is lost when the Rap1 gene is deleted from them.

To prove that this particular cell population is the true site of metformin’s action, the researchers used precise genetic tools to either delete or activate Rap1 only in the VMH neurons. Deleting Rap1 mimicked the glucose-lowering effect of metformin. Conversely, activating it was enough to block metformin’s therapeutic effect on glucose tolerance.

“This discovery changes how we think about metformin,” Fukuda said. “It’s not just working in the liver or the gut, it’s also acting in the brain. We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels. These findings open the door to developing new diabetes treatments that directly target this pathway in the brain.”

The possibility of tapping into metformin’s anti-aging potential was not lost on the researchers. “In addition, metformin is known for other health benefits, such as slowing brain aging,” Fukuda noted. “We plan to investigate whether this same brain Rap1 signaling is responsible for other well-documented effects of the drug on the brain.”

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Literature

[1] Lin, Y., Lu, W., He, Y., Fu, Y., Kaneko, K., Huang, P., Wang, C., Yang, Y., Li, F., Xu, Y., & Fukuda, M. (2025). Low-dose metformin requires brain Rap1 for its antidiabetic action. Science Advances.

[2] Diabetes Prevention Program Research Group. (2012). Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes care, 35(4), 731-737.

[3] Soukas, A. A., Hao, H., & Wu, L. (2019). Metformin as anti-aging therapy: is it for everyone? Trends in Endocrinology & Metabolism, 30(10), 745-755.

[4] Kaneko, K., Lin, H. Y., Fu, Y., Saha, P. K., De la Puente-Gomez, A. B., Xu, Y., … & Fukuda, M. (2021). Rap1 in the VMH regulates glucose homeostasis. JCI insight, 6(11), e142545.

Date Posted: August 1, 2025

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Rejuvenation Roundup July 2025

Summer is heating things up, both in the Northern Hemisphere and in the world of rejuvenation biotechnology. Here’s what’s happened in July.

Team and activities

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.

Interviews

Dr. David Furman on Inflammation and Aging: Dr. David Furman, who has been studying inflammation for many years at Stanford and the Buck Institute for Research on Aging, might be the best authority to talk to about inflammation and aging.

Gabriel Cian on Investment and the 2060 Longevity Forum: In this Lifespan interview, we spoke with Gabriel Cian, founder of the 2060 Longevity Forum, about healthspan innovation, credibility, bottlenecks, and opportunities.

Advocacy and Analysis

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.

Research Roundup

Study Discovers a Mammalian Mechanism of Tissue Regeneration: Scientists have analyzed the differences between mammalian species that can regrow ear tissue after injury and those that cannot. Their findings can pave the way for novel regenerative therapies.

Healthspan Effects of an Anti-Aging Vaccine on Mice: The researchers of a recent study published in Aging Cell described their novel CD38 peptide vaccine, which improved many measurements of physical health and prevented cognitive decline in aged mice.

Researchers Connect Cellular Markers to Physical Well-Being: In Aging Cell, a team of researchers has described how the health of skin fibroblasts relates to physical and functional ability.

Fixing Sugar Metabolism Shows Promise Against Dementia: Scientists have shown that aberrant metabolism of glycogen in neurons is linked to the accumulation of harmful tau protein. Caloric restriction, genetic interventions, and small molecules might help.

Five Hallmarks of Stem Cell Aging Proposed: In Cell Stem Cell, a trio of reviewers has proposed five hallmarks that are specific to the aging of stem cells.

Inflammaging Might Not Be Universal Across Populations: By comparing data from industrialized and non-industrialized societies, a new study calls into question some assumptions about the relationship between inflammation and aging.

Molecular Similarities Between Cigarette Smoking and Aging: Researchers have analyzed molecular patterns from different tissues obtained from over 700 people and learned that smoking acts as an aging accelerator.

Senolytics May Affect Inflammation-Related Cognitive Decline: Researchers have found that inflamed, senescent microglia prune too many synapses in the hippocampus and demonstrated that a senolytic compound can ameliorate this process in Aging Cell.

Scientists Successfully Edit Mitochondrial DNA: A new study demonstrates that novel gene-editing tools can correct disease-causing mutations in mitochondrial DNA in primary human cells.

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.

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.

A Hallucinogenic Mushroom Compound Extends Mouse Lifespan: Psilocybin, a psychedelic compound found in hallucinogenic mushrooms, extends cellular and organismal lifespan, even when administered later in life.

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.

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.

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.

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.

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.

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.

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.

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.

Rejuvenating Muscles in Mice With Senomorphic Treatment: A recent study investigated senescence in mouse and human skeletal muscle tissue, demonstrating that the antiviral drug maraviroc reduces senescence and improves muscle health in aged mice.

Senescent Cells, Osteoporosis, and Alzheimer’s Are Linked: Researchers publishing in Nature Aging have discovered how Alzheimer’s-related protein aggregates are also related to senescent cells and osteoporosis.

A high-fiber diet mimics aging-related signatures of caloric restriction in mammals: These results indicate that the high-fiber diet confers promising benefits for metabolic homeostasis and represents a valuable candidate for further health and aging studies.

Optimal exercise interventions for enhancing cognitive function in older adults: a network meta-analysis: Different exercise modalities provide domain-specific cognitive benefits in healthy older adults.

Differential associations of dietary inflammatory potential, antioxidant capacity, and Mediterranean diet adherence with biological aging:This study provides robust evidence that dietary pro-inflammatory potential, antioxidant capacity, and Mediterranean diet adherence exhibit independent and differential associations with biological aging.

Linking dietary creatine to DNA methylation-based predictors of mortality in individuals aged 50 and above: These findings highlight creatine’s potential as a modifiable dietary factor promoting healthy aging and longevity.

Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice: The detrimental effects of rapamycin on glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.

GrimAge and GrimAge2 Age Acceleration effectively predict mortality risk: a retrospective cohort study: These findings suggest that both GrimAge and GrimAge2 are effective epigenetic biomarkers for mortality risk prediction and may be valuable tools in future ageing-related research.

Human clinical trial of plasmapheresis effects on biomarkers of aging (efficacy and safety trial): Plasmapheresis can rapidly change the levels of pro-inflammatory and other pro-aging molecules in the circulation. However, the selected protocol has not provided conclusive data supporting benefits. Based on epigenetic clock parameters, it may accelerate epigenetic aging.

Human umbilical cord-derived mesenchymal stromal cell exosomes ameliorate aging-associated skeletal muscle atrophy and dysfunction in SAMP10 mice: These findings indicate that hucMSC-Exos treatment ameliorated skeletal muscle atrophy and dysfunction via mitochondrial biogenesis, anti-apoptosis, and protein anabolism mechanisms.

A Machine-Learning Approach Identifies Rejuvenating Interventions in the Human Brain: These results demonstrate the platform’s ability to identify brain-rejuvenating interventions, offering potential treatments for neurodegenerative diseases.

Drug combination-wide association studies of cancer: These results demonstrate the platform’s ability to identify brain-rejuvenating interventions, offering potential treatments for neurodegenerative diseases.

Comparative efficacy of topical interventions for facial photoaging: a network meta-analysis: These findings provide evidence-based guidance for clinical decision-making in anti-photoaging therapy.

Advancing Geroscience Research – A Scoping Review of Regulatory Environments for Gerotherapeutics: The researchers did not identify any geroscience specific regulatory frameworks but identified barriers to their development.

The impact of cannabis use on ageing and longevity: a systematic review of research insights: While preliminary research suggests intriguing possibilities, more studies are needed to solidify the link between cannabis use and healthy aging in humans.

Nicotine Reprograms Aging-Related Metabolism and Protects Against Motor Decline in Mice: These findings suggest that life-long oral nicotine consumption reprograms aging-associated metabolism through regulation of systemic sphingolipid homeostasis, conferring resilience against age-related motor decline.

News Nuggets

Chugai and Gero Enter Into Research and License Agreement: Chugai Pharmaceutical Co., Ltd. and Gero PTE. LTD, a Singapore-based biotechnology company, announced today that they have entered into a joint research and license agreement to develop novel therapies for age-related diseases.

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.

Coming Up

Madrid Set to Become the Longevity Capital of Europe: We are thrilled to announce the second edition of the International Longevity Summit (www.TransVisionMadrid.com) in beautiful Madrid after the major success in 2024.

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Date Posted: July 31, 2025

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Senescent Cells, Osteoporosis, and Alzheimer’s Are Linked

Researchers publishing in Nature Aging have discovered how Alzheimer’s-related protein aggregates are also related to senescent cells and osteoporosis.

Beyond the brain

Why We Age: Loss of Proteostasis

The loss of proteostasis is the failure of the protein-building machinery of the cell and the accumulation of misfolded proteins, which is one of the root causes of age-related diseases, including Alzheimer's disease.
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The amyloid tangles that result from a loss of proteostasis are very well-known in the context of Alzheimer’s and other neurodegenerative diseases. However, amyloid fibrils can appear in many other organs, including the liver, kidneys, and heart [1]. When this occurs throughout the body, it is known as systemic amyloidosis, a potentially fatal condition [2]. Like other proteostasis diseases, this can be caused by rare genetic disorders but is most often linked to aging [3].

Interestingly, the incidence of proteostasis diseases seems to be linked between entirely different organs. Compared to an average person of the same age, someone with Alzheimer’s is more likely to have been suffering from bone loss well before Alzheimer’s was diagnosed [4]. In Alzheimer’s model mice, the rate of bone loss is above that of wild-type mice [5].

Despite some work being done in intervertebral and related tissues [6], the causes and consequences of amyloid deposition in bone have been the subject of very little previous work. These researchers sought to fill that gap, discovering a relationship between these amyloids and senescent cells.

Nerve amyloids affecting bone tissue

These researchers reared two variants of Alzheimer’s model mice and compared them to wild-type mice at 9 months of age. While the two variants did not share the exact same metrics, both types had prematurely aged bones. There were significant indicators of osteoporosis, including thinner and less dense bones, and they had fat deposits throughout their bones that wild-type mice did not.

The researchers found antibodies against amyloid beta (Aβ) in the bones of the Alzheimer’s mice. Their data suggested that these amyloids may have originated from nervous tissue, which implies that Alzheimer’s itself causes some of this premature bone aging. However, older wild-type mice, which do not get Alzheimer’s, also had Aβ deposits. In both cases, these Aβ deposits formed rings around fat cells in the bone marrow, which prompted the researchers to surmise that the fat cells were stabilizing them.

These fat cells were found to have substantial markers of cellular senescence in Alzheimer’s mice, including the well-known p16, p21, and SA-β-gal. p19, a regulator of the relationship between p21 and the tumor suppressor p53, was also upregulated, as was the DNA damage marker γH2AX. The relationship between CEBPα, which drives the formation of fat cells in bone tissue, and p19 was found to be a crucial part of this accelerated senescence.

Further experiments found that it was these senescent cells that were causing the bone loss. The researchers transplanted these fat cells from Alzheimer’s model mice into 4-month-old wild-type mice alongside a control group that had transplants from other wild-type mice. The senescent fat cells derived from the Alzheimer’s mice secreted signals (the SASP) that led to significant bone loss, and removing these cells with the senolytic combination of dasatinib and quercetin ameliorated some of the damage.

A SASP factor can cause amyloid aggregation

An antibody array found that the main factor involved in this bone loss was SAP/PTX2, which was found to be largely localized to the senescent fat cells. Administering either the dasatinib and quercetin combination or ruxolitinib, a compound that inhibits the SASP, to Alzheimer’s mice was sufficient to reduce the level of SAP to that of the wild-type mice. Importantly, SAP was found to be directly related to amyloid formation itself; introducing SAP to unaggregated amyloid beta peptides caused them to aggregate.

The researchers then tested another compound, CPHPC, which directly targets SAP. This compound was found to aid against both Aβ deposition and bone loss. Osteoclasts, cells that are responsible for destroying bone, were significantly less prevalent in the CPHPC-treated Alzheimer’s mice.

This direct relationship between a SASP factor and Aβ deposition is surprising and suggests new potential therapies. While this approach does not affect the production of amyloids within cells, a SASP factor that causes these amyloids to aggregate is a clear target. However, this approach has not yet been tested in human beings, it is not clear if other amyloids are involved, and it has yet to be determined if senolytics, senomorphics, or compounds such as CPHPC may be effective against amyloid-related osteoporosis.

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Literature

[1] Gertz, M. A., Comenzo, R., Falk, R. H., Fermand, J. P., Hazenberg, B. P., Hawkins, P. N., … & Grateau, G. (2005). Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis. American journal of hematology, 79(4), 319-328.

[2] Gertz, M. A., & Dispenzieri, A. (2020). Systemic amyloidosis recognition, prognosis, and therapy: a systematic review. Jama, 324(1), 79-89.

[3] Hipp, M. S., Kasturi, P., & Hartl, F. U. (2019). The proteostasis network and its decline in ageing. Nature reviews Molecular cell biology, 20(7), 421-435.

[4] Tan, Z. S., Seshadri, S., Beiser, A., Zhang, Y., Felson, D., Hannan, M. T., … & Kiel, D. P. (2005). Bone mineral density and the risk of Alzheimer disease. Archives of neurology, 62(1), 107-111.

[5] Dengler-Crish, C. M., Ball, H. C., Lin, L., Novak, K. M., & Cooper, L. N. (2018). Evidence of Wnt/β-catenin alterations in brain and bone of a tauopathy mouse model of Alzheimer’s disease. Neurobiology of aging, 67, 148-158.

[6] Mihara, S., Kawai, S., Gondo, T., & Ishihara, T. (1994). Intervertebral disc amyloidosis: histochemical, immunohistochemical and ultrastructural observations. Histopathology, 25(5), 415-420.

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.

Yes I will donate❤️

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.”

Yes I will donate❤️

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.

Yes I will donate❤️

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.

Yes I will donate❤️

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.

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