An AI-Based System Has Found a Potential Longevity Drug

Date Posted: November 27, 2025

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An AI-Based System Has Found a Potential Longevity Drug

In a preprint published in bioRxiv, Prof. Vadim Gladyshev and a team of researchers have used an artificial intelligence-based system to discover a wide variety of potential interventions, including a drug that significantly improves biomarkers of frailty in mice.

Repurposing previous data

Previous research efforts have created a massive dataset in the form of the Gene Expression Omnibus (GEO), which contains the results of a great many experiments related to potentially disease-modifying drugs, many of which are tissue-specific [1]. These researchers refer to this dataset as a “massive missed opportunity” in aging research, because the vast majority of the experiments in the GEO were unrelated to aging and their data was never investigated in that context.

However, investigating all of that data by hand is practically impossible. These researchers note that modern LLMs can “autonomously generate hypotheses, execute complex analytical pipelines, synthesize findings across multiple data sources, and identify patterns that human researchers might overlook.” Combining that ability with the latest generation of clocks, including causality-based clocks such as AdaptAge, CausAge, and DamAge [2], may yield insights that would have simply gotten lost in the noise.

To that end, these researchers created ClockBase Agent, which uses over two million human and murine samples, including both RNA sequencing and epigenetic measurements, and 40 separate aging clocks. Unlike previous efforts in this area, which used simpler AI systems to simply link compounds to improvements in aging biomarkers, ClockBase is built to exhibit real agentic behavior: it uses an LLM to generate hypotheses about this data, then verifies these hypotheses with more in-depth examinations of both the raw data and the literature from which the data was derived.

Much of the data agrees with existing databases

Unsurprisingly, the clocks showed their natures rapidly. The researchers found that first-generation clocks, which were simply meant to estimate chronological age, were strongly correlated with each other, while healthspan-based clocks such as GrimAge were indeed correlated with healthspan and had data clusters accordingly.

Of a total of 43,529 interventions, which included genetics, diseases, pharmacology, and environment, the researchers’ AI model identified 5,756 that were statistically likely to have age-modifying effects. One was the knocking out of IFR4, which is essential in immune cell differentiation, and another was the knockout of Mettl3, which methylates RNA.

The expression of Bach2, which keeps T cells quiescent, was also associated with reduced aging, as was the overexpression of miR-155, a result that the AI gave an extraordinarily low p-value (2.69 * 10^-10), reflecting very high confidence, and the researchers found surprising due to miR-155’s pro-inflammatory effects. On the other hand, the disruption of hedgehog signaling, which is required for tissue homeostasis, and the knockout of H3K9 methyltransferases substantially increased aging; the latter result is wholly unsurprising due to H3K9’s effects on methylation. Most of its results agreed with the existing GeneAge database, and the few that did not could mostly be explained by the negative, age-increasing effects of knocking out “anti-longevity” genes such as Mtor.

The AI agreed wth the consensus that rapamycin and metformin reduce biological aging. It also found that ouabain, a little-known but established senolytic, also substantially reduces aging according to these clocks, as does the dyslipidemia drug fenofibrate. The immunomoulator Serpina3n was strongly linked to reduced aging, while the immune activator 3M-052 accelerated it. Many of the drugs the model identified are already approved by the FDA; unfortunately, it found that nearly two-thirds of the drugs it identified accelerate aging rather than slow it down. Only five of its results were found in the existing DrugAge database, which agreed with the direction of all five.

This model also found that environmental causes led to biological effects. A combination of mechanical overload, which may reflect exercise practices such as resistance training, along with senolytic administration was substantially associated with reductions in age. Hypoxia, the ischemia-reperfusion injury associated with heart attacks and their treatment, infection with viruses, and some metabolic disorders also accelerated age. Exposing embryos to high-intensity light sources accelerates their aging as well.

Overall, the researchers found that their agent found a substantial amount of both corroborating information and potentially actionable new information, stating that it “reveals a substantial set of new intervention candidates for aging research.” While the AI did make a handful of mistakes in its generation of hypotheses, such as being tripped up on clock age versus chronological age and some issues relating to control groups and treatment groups in complex experiments, its overall results provide an immense potential starting point for further work.

Verifying the AI’s data

The researchers took a crucial step to determine if their model was accurate: they used ouabain, the senolytic that the AI identified as being age-decelerating, in their own experiment with standard, 20-month-old, Black 6 mice. They followed the same protocol as the ouabain experiment that the AI had used to generate its conclusion.

In this experiment, the treatment group was far healthier than the control group after three months of intermittent ouabain exposure. This included metrics of frailty, cognitive ability, and fur condition. Their hearts functioned better, as did the microglia in some but not all brain regions. In total, the AI model had correctly identified ouabain as a potential age-modifying drug.

Of course, this was a murine result published in a preprint paper, and ouabain and many of the other interventions will have to go through further experiments and clinical trials before they can be confirmed as treatments and applied to human beings. The AI’s occasional flaws in reasoning mean that, despite the tremendous advances in this field over the past couple of years, it still cannot be fully relied upon to yield perfectly accurate information. However, it is clearly an invaluable tool in giving researchers critical clues that they would probably never have found without it.

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Literature

[1] Edgar, R., Domrachev, M., & Lash, A. E. (2002). Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic acids research, 30(1), 207-210.

[2] Ying, K., Paulson, S., Reinhard, J., de Lima Camillo, L. P., Träuble, J., Jokiel, S., … & Biomarkers of Aging Consortium. (2024). An open competition for biomarkers of aging. bioRxiv.

Date Posted: November 26, 2025

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The Roles of Phenylalanine and Tyrosine in Lifespan

A recent study investigated the impact of two amino acids, phenylalanine and tyrosine, on lifespan using UK Biobank data. The researchers reported an association between tyrosine and shorter lifespan, with sex-specific differences. The results for phenylalanine were more inconsistent [1].

One by one

Model animal research has shown that protein restriction can extend lifespan. However, proteins are complex molecules built from 20 different amino acids, and to determine whether it is one or more amino acids that impact healthspan and lifespan, researchers need to investigate them individually.

For example, we recently reported that dietary methionine restriction improves healthspan and that dietary isoleucine restriction boosts lifespan in mice. On the other hand, increased protein intake, particularly leucine, can exacerbate atherosclerosis, an age-related disease. Also, some amino acids might be needed in greater amounts to help protect against aging-associated diseases. For example, we have reported that increasing glutathione levels with GlyNAC, a supplement that combines glycine and cysteine, significantly reverses age-related cognitive decline in naturally aged mice. Those reports point to the complex role of amino acids in aging and age-related diseases along with the need to investigate their individual impacts on healthspan and lifespan.

In this study, the researchers focused specifically on two amino acids, phenylalanine and tyrosine, and their impacts on lifespan, including sex-specific differences.

Tyrosine is an essential metabolite in many metabolic processes and a precursor to neurotransmitters such as dopamine, norepinephrine, and epinephrine, which regulate mood, cognition, and stress responses [2]. Animal experiments suggest that tyrosine restriction plays a role in lifespan extension, potentially by suppressing insulin signaling and the mTORC1 pathway [3].

Phenylalanine is the precursor of tyrosine. Its elevated levels were linked to such detrimental processes as telomere loss [4], inflammatory disease [5], and type 2 diabetes [6]. Its toxic derivative has been shown to shorten the lifespan of model organisms [7].

For the investigation, the researchers used a UK Biobank cohort of 272,475 participants that had all the necessary information for this analysis. However, they note some limitations of the dataset. For example, the available data included only a single measurement of tyrosine and phenylalanine levels. Therefore, they were unable to test the impacts of changes in these amino acid levels over time.

They also note that the observational design of UK Biobank data is susceptible to confounding factors arising from differences in participants’ health and socioeconomic status, the latter being especially difficult to measure accurately. To address that, they also used Mendelian randomization (MR), which uses “genetic variants as instruments, which are less affected by socioeconomic positions.” However, using these different analyses might yield different results that need to be interpreted in light of the data used in each test.

The kind of amino acid makes a difference

The initial analysis of UK Biobank data, adjusted for multiple confounders, showed an association between plasma phenylalanine and elevated all-cause mortality in the whole population and in men and women when analyzed separately. For tyrosine, the researchers also observed an association between plasma tyrosine and a higher risk of all-cause mortality in the whole study population and in men but not in women.

When specific causes of death were investigated, the analysis revealed positive associations between phenylalanine, but not tyrosine, and both cardiovascular disease (CVD) and cancer mortality, suggesting a role for phenylalanine in molecular pathways related to cardiovascular health and carcinogenesis.

Further analysis investigating the relationship between the two amino acids showed a link between a higher tyrosine-to-phenylalanine ratio and a lower overall risk of all-cause mortality in the general population and in women but not in men.

Using genetic data

A genetic analysis identified gene variants that are significantly linked to phenylalanine and tyrosine. The researchers narrowed their list to several single-nucleotide polymorphisms (SNPs, genetic variants with a single DNA base difference) and used them as instruments in their analysis. Those SNPs were “located within genes critical for amino acid metabolism, transport, and regulation.”

Then, they used those SNPs in an MR analysis to estimate their effects on lifespan. “Genetically predicted higher phenylalanine was related to longer lifespan in men but not related to lifespan in overall analysis or in women.” Those associations were the same even when different analytics methods were used.

“Genetically mimicked higher tyrosine levels were linked to a shorter lifespan in the overall population and in both sexes” in two types of analysis, and there was the same trend in the same way in the other analysis. They also conducted a similar analysis using data from different populations outside the UK, obtaining comparable results.

Following an MR analysis that included both amino acids, the researchers found that phenylalanine didn’t affect lifespan when controlling for tyrosine. However, the effect of tyrosine, associated with shorter lifespan in men but not women persisted even after controlling for phenylalanine.

Tyrosine reduction as a possible intervention

Summarizing, the researchers observed an association between tyrosine and shorter lifespan in observational and MR studies, which was independent of phenylalanine. The effect was stronger in men than in women, possibly due to sex-specific differences or insufficient statistical power in some tests to detect it. Future studies with larger sample sizes might confirm or debunk these results.

On the other hand, the phenylalanine results were less consistent. An observational analysis found an association between plasma phenylalanine and elevated all-cause mortality, but in an MR analysis, in which the researchers controlled for tyrosine, phenylalanine did not affect lifespan.

The researchers suggest that, based on their results and on rodent studies that also implicate tyrosine in lifespan, “reducing tyrosine in people with elevated concentrations may contribute to prolonging lifespan”. However, there is a need for a better understanding of the molecular mechanisms that link tyrosine restriction to lifespan extension.

Yes I will donate❤️

Literature

[1] Zhao, J. V., Sun, Y., Zhang, J., & Ye, K. (2025). The role of phenylalanine and tyrosine in longevity: a cohort and Mendelian randomization study. Aging, 17(10), 2500–2533.

[2] Fernstrom, J. D., & Fernstrom, M. H. (2007). Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. The Journal of nutrition, 137(6 Suppl 1), 1539S–1548S.

[3] Kosakamoto, H., Sakuma, C., Okada, R., Miura, M., & Obata, F. (2024). Context-dependent impact of the dietary non-essential amino acid tyrosine on Drosophila physiology and longevity. Science advances, 10(35), eadn7167.

[4] Eriksson, J. G., Guzzardi, M. A., Iozzo, P., Kajantie, E., Kautiainen, H., & Salonen, M. K. (2017). Higher serum phenylalanine concentration is associated with more rapid telomere shortening in men. The American journal of clinical nutrition, 105(1), 144–150.

[5] Neurauter, G., Schröcksnadel, K., Scholl-Bürgi, S., Sperner-Unterweger, B., Schubert, C., Ledochowski, M., & Fuchs, D. (2008). Chronic immune stimulation correlates with reduced phenylalanine turnover. Current drug metabolism, 9(7), 622–627.

[6] Guasch-Ferré, M., Hruby, A., Toledo, E., Clish, C. B., Martínez-González, M. A., Salas-Salvadó, J., & Hu, F. B. (2016). Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis. Diabetes care, 39(5), 833–846.

[7] Dato, S., Hoxha, E., Crocco, P., Iannone, F., Passarino, G., & Rose, G. (2019). Amino acids and amino acid sensing: implication for aging and diseases. Biogerontology, 20(1), 17–31.

Date Posted: November 25, 2025

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Fixing Lysosomes Improves Blood Stem Cell Function

In a recent study, scientists have demonstrated that lysosomal dysfunction actively decreases the potency of hematopoietic stem cells. Calming lysosomes reversed this process, opening avenues for new treatments [1].

Few and far between

Hematopoietic stem cells (HSCs) are rare and precious: they produce blood progenitor cells, which, in turn, produce all differentiated blood cells. With age, HSC function gets increasingly dysregulated, which has been linked to immune decline, increased inflammation and atherosclerosis, and higher cancer risk [2].

One particular consequence is clonal hematopoiesis, which occurs when some HSCs acquire mutations that make them more reproductive. However, their progeny, which overwhelms the blood cell pool, is usually of lesser quality. Clonal hematopoiesis is increasingly recognized as an important driver of aging and mortality [3], especially in the oldest people.

Lysosomes are the cell’s recycling plants: they break down worn-out proteins, lipids, and even whole organelles into reusable building blocks, keeping the cell clean, fueled, and functional. Scientists have been unsure whether lysosomal dysfunction, which worsens with age, is a causal driver of HSC aging. A new study from the Icahn School of Medicine at Mount Sinai, published in Cell Stem Cell, asks the question: do lysosome changes in old HSCs actively cause dysfunction, and if so, can reversing these changes restore youthful HSC function?

The lysosome connection

The team took mouse HSCs from young (8-week) and old (22- to 24-month) mice. First, they sorted the cells into more quiescent/potent and more activated/less potent subsets. The researchers then analyzed lysosomes and found that lysosomal function was markedly dysregulated in aged cells and present across both subsets, pointing to a general aging-related decline.

Old HSCs showed reduced lysosomal mass and had lysosomes with a lower pH than normal (hyperacidification). The older lysosomes overall had leakier, compromised membranes. Surprisingly, they were also more active compared to lysosomes in young cells, like older, more polluting engines operating at higher speeds.

Inhibiting the enzyme v-ATPase, a proton pump that acidifies lysosomes, with a compound called ConA dampened lysosomal activity and normalized pH levels. Markers of lysosomal integrity bounced back as well. This showed that lysosomal defects in old HSCs are at least partly driven by v-ATPase and can be reversed.

Old HSCs had higher levels of mTORC1, a nutrient-sensing kinase that pushes cells toward growth and cycling. Essentially, hyperactive lysosomes helped keep old HSCs metabolically active. Inhibiting v-ATPase reduced mTORC1 expression and its lysosomal colocalization back toward young levels associated with a restrained, quiescent metabolism.

The researchers also found that lysosomes in old HSCs mis-process damaged mitochondria. As a result, mitochondrial DNA (mtDNA) escapes into the cytosol. Cells mistake cytosolic mtDNA for foreign (such as viral) DNA and activate the cGAS-STING inflammatory pathway. ConA reduced extramitochondrial mtDNA and suppressed cGAS-STING activation.

Rebuilding the blood system

For their in vivo experiments, the scientists took HSCs out of mice and cultured them with ConA for four days. Mice were then irradiated to wipe out their bone marrow – much like after high-dose chemotherapy – so transplanted stem cells had to rebuild the entire blood system from scratch.

A small number of treated old HSCs were transplanted back into these mice, together with a much larger number of ordinary bone-marrow cells from a healthy mouse. The ability of HSCs to produce substantial progeny despite the competition would indicate success. Another group received sham-treated HSCs.

ConA pretreatment boosted old HSC output up to 16-fold compared to sham-treated cells over the 21-week follow-up, showing that the cells regained the ability to sustain blood production long-term, not just transiently. Several recipients of sham-treated old HSCs died by 21 weeks, while survival in the ConA group was higher. ConA also increased lymphoid compared to myeloid output from old HSCs, reversing this hallmark of clonal hematopoiesis, and significantly increased the number of donor-derived T and B cells.

“Our findings reveal that aging in blood stem cells is not an irreversible fate. Old blood stem cells have the capacity to revert to a youthful state; they can bounce back,” said Saghi Ghaffari, MD, Ph.D., Professor of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine. “By slowing down the lysosomes and reducing their acidity, stem cells became healthier and could make new balanced blood cells and new stem cells much more effectively. By targeting lysosomal hyperactivity, we were able to reset aged stem cells to a younger, healthier state, improving their ability to regenerate blood and immune cells.”

“Lysosomal dysfunction emerges as a central driver of stem cell aging,” he added. “Targeting this pathway may one day help maintain healthy blood and immune systems in the elderly, improve their stem cells for transplantation, and reduce the risk of age-associated blood disorders and perhaps have an effect on overall aging.”

Yes I will donate❤️

Literature

[1] Tasleem Arif, Jiajing Qiu, Hossein Khademian, Anusree Lohithakshan, Anagha Menon, Vijay Menon, Mary Slavinsky, Maxime Batignes, Miao Lin, Robert Sebra, Kristin G. Beaumont, Deanna L. Benson, Nikolaos Tzavaras, Mickaël M. Ménager, Saghi Ghaffari. (2025). Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells, Cell Stem Cell

[2] Kasbekar, M., Mitchell, C. A., Proven, M. A., & Passegué, E. (2023). Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands. Cell Stem Cell, 30(11), 1403-1420.

[3] Jaiswal, S., & Ebert, B. L. (2019). Clonal hematopoiesis in human aging and disease. Science, 366(6465), eaan4673.

Date Posted: November 24, 2025

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Nanoparticles Improve Intercellular Mitochondrial Transfer

Scientists have created “nanoflowers” that nudge donor cells to produce more mitochondria, which can then be transferred to recipient cells to boost their mitochondrial function [1].

Mitochondrial transfer is difficult to improve

Energy is required for life, and most energy in our cells is produced by mitochondria. When these organelles start to falter, it’s a sign of trouble. Numerous diseases are linked to mitochondrial dysfunction, which is a hallmark of aging.

Intercellular mitochondrial transfer (IMT) is a natural rescue mechanism that is defined as stressed cells receiving healthy mitochondria from their neighbors, especially mesenchymal stem cells (MSCs), via tunneling nanotubes (TNTs), extracellular vesicles, or gap junction channels [2]. However, transfer rates are low, and most current methods to boost them are cumbersome and may involve genetic engineering.

In a new study from Texas A&M University, published in Proceedings of the National Academy of Sciences, the researchers describe a novel method for improving IMT, which involves some nanotechnological wizardry.

“Nanoflowers” boost mitochondrial output

The team looked for ways to improve mitogenesis in MSCs, reasoning that this might boost their ability to donate mitochondria. They started with molybdenum sulfide (MoS₂) and subjected it to “defect engineering.” This process takes out some of the sulfur atoms, exposing molybdenum atoms that have electrons to donate. Molybdenum is a transition metal, which means it has variable oxidation states and can either donate or accept electrons depending on the context.

This unusual material can mimic the enzyme catalase, neutralizing ROS (reactive oxygen species). ROS react with various biomolecules, such as proteins, lipids, and DNA, damaging them and creating oxidative stress, which hurts mitochondrial function [3].

The exposed molybdenum atoms act as traps and catalysts for ROS molecules. For instance, when a molecule of hydrogen peroxide (H₂O₂), the most ubiquitous ROS, approaches the site, it accepts two electrons from a molybdenum atom, separating the extra oxygen atom from the peroxide and leaving behind water. When the next H₂O₂ molecule approaches the site, another oxygen atom pulls itself away from the peroxide and becomes bound to the first trapped oxygen atom, forming free diatomic oxygen (O₂) and another molecule of water while returning the electrons to the molybdenum.

For further improvement, the researcher designed a process of MoS₂ self-assembling into “nanoflowers”, delicate structures that greatly increase the material’s surface-to-weight ratio. MSCs were able to take nanoflowers up, which decreased ROS levels and improved mitochondrial output. After seven days of treatment, the amount of mitochondrial DNA, a marker of mitochondria abundance, doubled, and the production of ATP, the “energy currency” of the cell, increased as well.

“MoS₂ nanoflowers with atomic vacancies activate the PGC-1α pathway by modulating cellular ROS levels and stimulating the SIRT1 signaling pathway,” the paper says. “This activation leads to increased mitochondrial biogenesis and enhanced cellular bioenergetics.” In other words, by clearing up ROS, nanoflowers triggered cells to signal that stress has decreased and mitochondria production can be ramped up.

“MitoFactories” to the rescue

To assess the effectiveness of IMT, the researchers induced mitochondrial damage in smooth muscle cells. “Nanoflower”-treated MSCs, which the researchers refer to as “MitoFactories,” were several-fold more effective in transferring their increased mitochondrial load into their damaged neighbors than untreated controls.

“We have trained healthy cells to share their spare batteries with weaker ones,” said Dr. Akhilesh K. Gaharwar, a professor of biomedical engineering and a senior author. “By increasing the number of mitochondria inside donor cells, we can help aging or damaged cells regain their vitality – without any genetic modification or drugs.”

“The several-fold increase in efficiency was more than we could have hoped for,” added Ph.D. student John Soukar, lead author of the paper. “It’s like giving an old electronic a new battery pack. Instead of tossing them out, we are plugging fully-charged batteries from healthy cells into diseased ones.”

Putting new mitochondria to work

The damaged recipient cells not just successfully accepted mitochondria from the “MitoFactories” via TNTs, but also put them to work, integrating them into their mitochondrial network. Enhanced mitochondrial transfer restored cellular function and survivability to a notable degree. Interestingly, undamaged recipient cells also benefited from improved TNT, showing higher respiratory capacity and ATP production.

“This is an early but exciting step toward recharging aging tissues using their own biological machinery,” Gaharwar said. “If we can safely boost this natural power-sharing system, it could one day help slow or even reverse some effects of cellular aging.”

The strictly in vitro design was an obvious limitation of this study. In a more realistic setting, especially in an aged, fibrotic tissue, donor cells might have been unable to approach the recipient’s cells to initiate IMT. However, this is an exciting proof of concept, and the researchers are optimistic.

“You could put the cells anywhere in the patient,” Soukar said. “For cardiomyopathy, you can treat cardiac cells directly – putting the stem cells directly in or near the heart. If you have muscular dystrophy, you can inject them right into the muscle. It’s pretty promising in terms of being able to be used for a whole wide variety of cases, and this is just the start. We could work on this forever and find new things and new disease treatments every day.”

Yes I will donate❤️

Literature

[1] Soukar, J., Singh, K. A., Aviles, A., Hargett, S., Kaur, H., Foster, S., … & Gaharwar, A. K. (2025). Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency. Proceedings of the National Academy of Sciences, 122(43), e2505237122.

[2] Spees, J. L., Olson, S. D., Whitney, M. J., & Prockop, D. J. (2006). Mitochondrial transfer between cells can rescue aerobic respiration. Proceedings of the National Academy of Sciences, 103(5), 1283-1288.

[3] Guo, C., Sun, L., Chen, X., & Zhang, D. (2013). Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural regeneration research, 8(21), 2003-2014.

Date Posted: November 21, 2025

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George Church on Building “Scientific Superintelligence”

George Church, a Harvard professor and a famed geroscientist, is also known as a serial entrepreneur who has co-founded dozens of biotech companies. While Church maintains that he’s involved in them all, one company has been seeing an unusual amount of his attention: Lila Sciences, where he assumed the role of Chief Scientist.

On its website, Lila sets a lofty goal: to build a “Scientific Superintelligence.” Practically, this involves creating an array of AI models and, perhaps Lila’s defining feature, building huge robotic labs to quickly test AI-generated hypotheses and feed the data back into the model.

This company, founded in 2023, has raised $550 million and is now valued at $1.3 billion. It has already made several promising discoveries and appears well on its way to revolutionize the way we do science. We spoke with Dr. Church to learn more about this giant startup and his role in it.

You’ve co-founded many startups, but usually you retain an advisory role without investing too much energy in the company. With Lila, things seem different. You’re the chief scientist, and you said in an interview that you really want to invest a lot of your time in Lila. What’s different this time?

With previous companies, I have put a fair amount of effort into them, at least for periods of time, and they’re all advisory roles when you come right down to it. Even my own laboratory at Harvard Medical School is an advisory role.

But Lila is special in the sense that I’ve been working on computational biology and AI for many years, and I keep looking around for the big players. Who’s got the most interesting story that could conceivably fit in with other things that I’m trying to do, like longevity? Lila is not a longevity company, but it is a science AI company.

In particular, most of the AI companies are scraping the internet and seeing what they can do to use natural language processing to sort through what’s in the abstracts and maybe even the supplementary material for articles. Lila is using that a little bit, but by far the biggest component is new empirical data. So, rather than the open data that everybody has, this is to develop new proprietary data.

It’s partly based on my observation that every new technology we develop, within the first year or so, can redo almost everything in history up to that point in that field and then start multiplying it by factors of 10, so there’s no reason to try to scrape the poorly configured ancient history. It’s better to go forward where you’ve constructed it so that it’s maximally compatible with AI and with whatever ultimate applications you have in mind. That’s a big game changer for me. It struck me as the best thing you can do with AI.

In fact, there are other things you can do with AI that I think are not as useful and potentially a little bit more dangerous. I’m not a doomsayer or anything, but I’m just saying the ratio of benefit to risk is not appealing for going after artificial general intelligence. That’s not as likely to benefit society as just working on AI applied to science.

Here, I want to quote a press release from Lila. It says, “Lila’s mission is to responsibly achieve scientific superintelligence.” So, they are talking about superintelligence.

Scientific, not general superintelligence.

Still, “responsibly” implies that this can also be done irresponsibly and probably do some damage. So, how do you do it responsibly, and what could happen if we fail?

I think the first step in doing it responsibly is keeping the focus narrow. In other words, if you’re dealing with a natural intelligence (a group of people) and you give them total power, infinite resources, and no guidance on what they’re going to do with it, there’s a certain chance they’ll go rogue. I think it’s even more so if you’re dealing with an intelligence that’s completely alien, but that’s not what we’re doing.

We’re not empowering a superintelligence to consider whether humans are the best thing or not. That’s a dangerous question, at least for starters, until the new intelligence has had the time that the old intelligence has had to get adjusted to the real world and to evolve. So, you don’t want to just rush into it and say, “Okay, here are the keys to the kingdom,” and start asking philosophical questions that can lead to extermination. You want to keep it narrow.

Beyond that, “responsibly” means to make sure that you are being transparent about it and make sure that software is capable of explaining why it’s doing things.

About that: it’s always interpretability versus the model’s power. Where are you in this debate? Would you prefer a weaker but more interpretable AI or a stronger but less interpretable one?

I lean on the interpretability side. It’s not an either-or, but… we’re in science. Few engineers are willing to just pull a rabbit out of a hat, just a black box. Scientists and engineers, by and large, want to know the mechanism. The FDA likes to know mechanisms. Typically, the autocatalytic loop where you learn something and then you invent something is better if it’s mechanistically grounded. So, I lean pretty heavily in the direction of interpretability, explainability, transparency, et cetera, and also it’s safer.

I just honestly think that we will soon be faced with this dilemma, where we will have to choose between the power of the model to do things and its actual interpretability, but maybe we’re not there yet.

If you look at the human scientist experience, the most powerful sciences are the ones that are better articulated mechanistically on a solid foundation rather than black boxes. The black boxes tend to include artifacts, dead ends. Most of the progress in science and engineering has been part of community efforts with strong mechanistic underpinnings.

Let’s move to Lila’s model. Can you give me any more details? For instance, is the reasoning happening on the human language level?

Well, it’s really models, plural. There’s the meta-model that I’ve already mentioned, which is obtaining proprietary data using new high-throughput methods. Then there is a language model where we interface with it the way essentially everybody interfaces with computers at this point, which is through natural language, but then there are specific models for each scientific enterprise.

We’re getting better and better at the meta-level of learning from the specific models to make the next specific model, but the bitter lesson is to not over-engineer and over-educate; it’s to let the data speak for themselves. I think that’s turned out again and again in the Lila experience. We’ve done about 12 different model systems, and in each case, there usually are some industry milestones or standards. We can ask, how do we stand? In almost every case, we’ve managed to exceed whatever the milestone points were at the time. These are wildly different fields of science, and we were able to pass the milestones. So, it probably means we’re on the right track.

We’ve seen before companies that are building foundation models in biology, companies that use AI to create drugs, and companies that are developing robotic labs. Sometimes they combine two of those. I don’t think I’ve ever seen a company that combines all three. You already said this is in part about getting proprietary data that you can feed into the model. Can you expand on this?

I think there are two conventional sources of large data. One of them is PubMed and things like that, and the other is theoretical. But as powerful as AI is, both at scraping the internet with natural language and at doing theoretical constructs, the empirical is something that’s often ignored.

We’ve gotten to an era where we can make very large libraries for certain fields of science. We can make material libraries; DNA, RNA, and protein libraries; cellular libraries, and they can be barcoded and multiplexed effectively. Then it becomes a question of how clever the human-AI team can be at analyzing and manufacturing these libraries.

With AAV, we designed a million changes that were highly diverse, but then how can you test them in a way that might not be easy to simulate with just computational simulations? So, we injected them directly into primates. Putting a million designed, not random, structures into primates simultaneously saves a lot of money relative to, say, doing a million primates each with a single injection, which was and still is the standard practice.

You can get things that are very hard to simulate. You can get it to be a hundred times better to go through the brain and detarget everything else. In principle, to simulate that in a computer, you’d have to know all the possible ligand binding sites throughout the endothelium and maybe throughout the entire “surface-ome” of the body. But instead, if you do it empirically, you get a perfect simulation, 100% correct, and you get it quickly. You get a million at once, and you can actually ask for all the different tissues. It’s like you got a million constructs times hundreds of different cell types.

This is sometimes called natural computing. It’s just as valid as von Neumann silicon computers or quantum computers. I think that’s a fundamental new capability. And you’re right, there are very few that try to do all these things at once, but there is something synergistic about it that we anticipated and we’re not disappointed.

Let’s go back for a second to that “scientific superintelligence.” I’m not asking if AI will replace human scientists. I’m asking how soon it will replace human scientists, and does it bother you in any way?

I think it’s kind of like saying, “How soon will automobiles replace runners and horsemen? How soon will jets replace all of those?” They don’t. It’s almost always a hybrid system. It’s like, “How soon will my cerebral cortex replace my cerebellum?” Why would you bother? They both do specialized tasks.

I think we already have, and we’ve had for years, things that computers could do way better than humans, starting with math, calculations, especially where speed is an issue, and then they did chess, Jeopardy, and Go. But there still are things where the hybrid system is likely to persist for science in particular.

I know this argument, but I think it’s too optimistic. It’s true that for our entire history, technology has been helping us, but now it looks like it’s finally going to replace us. Automobiles did replace horsemen almost completely, it’s just that those horsemen had other fields they could migrate to. This might not be the case this time. Do you honestly believe that for the foreseeable future, human scientists will remain relevant, will possess something that the models won’t?

The correct answer is I don’t know, but I still will speculate a little. First, we still are very efficient: the 20-watt brain versus megawatt GPU farms. Second, there’s considerable skepticism as to how hard it is to get the machine to think out of the box, or even think of what the box should be, to plan new experiments.

I also think humans are not necessarily a fixed target. It’s not like machines are progressing exponentially and biotechnology is standing still. They’re both progressing exponentially. To me, it’s not clear that humans won’t be augmented in some way. Given that we’re already ahead in energy efficiency, we might just get further and further ahead rather than falling behind. I’m not making a strong prediction there. I’m just saying there’s a lot of assumptions being made as to whether A will replace B or whether it’s going to be some hybrid system.

I agree. I just think that technically, creating such a hybrid system is really hard.

We already have a hybrid system. Every human is augmented and vice versa: the computer is currently augmented by the queries that we come up with. We’re coming up with a non-random set of prompts, and so far, it seems like we’re prompting the computer in ways that it wouldn’t prompt itself.

Even if Lila’s vision is fully realized in a few years, we will still have a lot of downstream bottlenecks. What are these bottlenecks that science will face, and what can be done about them?

Of course, one of the classic bottlenecks in therapeutics has been FDA approval or the equivalent in other countries, but that’s changing. I think the FDA has always been an agent of change, even if people sometimes don’t see it. The FDA loves it when scientists come across a new method or technology that is safe and effective.

For example, the COVID vaccine was a brand new technology, at least in terms of FDA approval, and it got approved very quickly in 11 months. Baby KJ got approved from birth to cure in seven months. I think that will probably still be a bottleneck, and rightly so, because we do want things to be safe and effective, but it starts to widen.

Typically, funding is a bottleneck until it’s not. I think clever scientists, and in the future, clever AI-plus-scientists, will come up with ways to reduce costs. For example, the cost of reading and writing DNA has dropped by 20 million-fold over less than two decades. And of course, electronics have a similar story over longer periods of time.

Certainly, a bottleneck for GPUs is energy. They’re talking more and more about locating near hydroelectric plants and investing in fusion power that doesn’t exist yet, but the alternative is to bring down the power consumption per FLOP. You want to get the FLOP-per-joule to be as low as possible. These are all bottlenecks that I think are addressable.

Another bottleneck that maybe hasn’t been considered very often (and also part of the reason we think that our biotechnology is static and the AI is dynamic) is that we’re not allowed to mess with the human brain very much. This is for ethical reasons, but it could be that that asymmetry may vanish in a variety of ways. It could be that silicon systems will demand more ethics, or “wetware” living brains might come up with a way that they can modify themselves that would be considered ethical, and they’ll probably converge on the same level of sentience and ethics of modification.

Let me know if you don’t want to be dragged into politics, but I’m trying to understand the net impact of the current administration. On one hand, it has cut down research funding, hurting a lot of people and research in our field. On the other hand, it seems to be very AI-friendly, and on the FDA level, they are now more open towards new testing modalities like organoids. Do you have an opinion on all that?

I don’t mind responding briefly. I’m a beneficiary on the organoid front. We do a lot of research in organoids, in particular brain organoids and embryos. I think that every now and then it’s helpful to science and society to stir things up a little bit. There will be winners and losers, and if there are enough losers, then there will be a backlash.

Both in science and in government, experiments can’t last for long, and they can’t fail for long. They can’t cause hardship for long. Science probably has a longer payoff that’s tolerated, especially if it’s inexpensive, but almost everything that the government does ends up being expensive and hurting somebody enough that it becomes a cause for a pushback.

So, I like the idea of doing experiments, even economic ones, but one has to be cautious that it’s a limited time. And you can see that the latest elections reflected some disappointment. In the midterms, we might see even more disappointment. It’s a feedback system. You do a radical experiment, and if you luck out, then everybody votes for you. Time will tell, but this is not something that’s going to play out in centuries. This is something that’s going to play out in months.

I have been thinking lately about the difference in public opinion on science and AI. It seems that the public generally loves science but vilifies AI. How do we get out of this?

It’s not quite that black and white. The public occasionally doesn’t like or trust certain kinds of science. With AI, part of it has to do with what Hollywood and screenwriters are writing about. If they see a new technology, it’s an opportunity to create both dystopias and utopias.

I think you need a large benefit as a prerequisite. One of the reasons GMOs were not popular is because the benefit wasn’t clear to many. The same thing is kind of true of AI. Most people either didn’t care about getting answers from Google, or if they did, the old pre-AI Google search was good enough. So, it really depends on convincing them that things that are positively affecting the economy and their health are actually due to AI.

Can you give me your vision for AI in biology in several years from now, a decade, maybe two? What will it be able to do? How would it change science and human aging?

I think AI has proven that it’s really useful for protein design, and protein structural prediction as well. And aging has proven that it is the ultimate disease. It involves possibly every subsystem of our physiology. So, it’s a perfect candidate for systems that can handle high complexity, and AI is one of those.

It’s also something you can de-black-box by doing experiments to test things. You can say, “Oh, this is how this is working.” In fact, AI can help design experiments that will not only screen these big libraries I was talking about, but also when you get the answers, you can have mechanistic interpretations, and you can test them.

It’s not that I disagree, I just think that everything about AI is a race. So maybe we will be able, theoretically, to de-black-box everything. We might just not have the time and the resources to do it because everyone’s racing to the goal.

That’s a fair statement, but it could be that the people that get to the goal faster are the ones that are working on mechanisms. It’s not incompatible with the history of science. Every now and then, people come up with a clever way to go a little bit faster.

It’s going to be empirical, and I think that we’re well on our way to solving some of the big engineering tasks that we need to get both longevity and age reversal. Aging reversal or disease reversal is what’s going to get FDA approval, and longevity is going to come along for the ride.

I think we have these exponential biotechnologies, which until recently did not depend on AI, while being exponential nonetheless. When you add them to AI, it might get us faster to mechanisms and faster to, let’s say, polypharmacy, where you need multiple drugs to handle all the different tissues, and each tissue might have a slightly different aging program.

So, you might need a very large number of drugs working in some kind of coherent way, and maybe devices to help the feedback loop. Those devices might be biological, or they might be electronic, or some hybrid.

It’s a great point about polypharmacy; I do see future anti-aging therapies as a complex array, where people will have to constantly do things to stay young (still worth it, though). So, fast forward to 10 years from now. Given how fast things are changing, do you even have this vision, this mental model of where we are going to be in a decade or two?

10 years used to be just barely enough time to do one clinical trial. Now you can do many clinical trials in parallel, but I think we soon will be doing clinical trials in less than a year. That means 20 years is 20 cycles of these things happening in parallel.

I think longevity and reversal of age-related diseases seem a lot less mysterious now than they used to, and all the exponential technologies are applicable. I would not be surprised if age-related diseases, and for that matter, diseases of poverty, will be easily solved in 20 years from now.

Yes I will donate❤️

Date Posted: November 20, 2025

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How Senescent Cells Encourage Melanoma Growth

Researchers publishing in Aging Cell have documented a key reason why older people are much more likely to get melanoma.

Why older people have significantly worse melanoma cases

While melanoma is much more treatable now than in the past, it still remains a serious danger. Melanoma can develop resistance to otherwise effective techniques [1], meaning that they only delay instead of permanently stop the disease.

Fortunately, the origins of melanoma are largely well-understood. The first thing that drives most melanoma cases is a point mutation of the BRAF gene [2]. This does not trigger melanoma by itself, but further mutations of other genes lead to malignancy [3].

The severity of melanoma is measured by its thickness, as it has been known for over half a century that thicker melanomas are much more dangerous [4]. The cancer’s transition from horizontal to vertical growth is associated with increasing mutation frequency [5], and, unsurprisingly, older people are typically diagnosed with considerably thicker melanomas than younger people are [6].

Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
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The researchers of this study have pinpointed cellular senescence as the most likely driver of this increase in severity, and significant previous work has been done to establish the connection between these cells’ potentially dangerous SASP secretions and melanoma [7]. However, that previous work did not completely elucidate the biological relationship between the two, which is what this study was created to find.

Melanoma is attracted to senescent cells

In their first experiment, the researchers confirmed a direct relationship between the prevalence of senescent skin fibroblasts and the incidence of melanoma. While p16 is a tumor suppressor and appears in both the benign and malignant portions of melanoma, it is bypassed by other cancerous mutations [8]. Injecting melanoma cells together with senescent or non-senescent fibroblasts into the skin of mice confirmed this relationship: the mice given senescent fibroblasts had tumors that were ten times as thick.

The researchers then looked into why this is the case. Cultivating melanoma in conditioned media that contains secretions from senescent fibroblasts, but not non-senescent fibroblasts, greatly increases the cancer’s growth. The researchers found two compounds of particular interest: GCL-2 and ENA-78, which melanoma cells were discovered to actively grow towards in a chemotaxic response, resulting in independent, unanchored growth. Neutralizing these compounds in conditioned media through antibodies greatly reduces the growth of melanoma, and enhancing GCL-2 production in non-senescent cells causes their related conditioned media to encourage the growth of this cancer.

These two compounds, which are considerably more abundant in the skin of older adults compared to young adults, are generated by senescent fibroblasts and not significantly by other cell types.

Further work found that GCL-2 is considerably more important than ECL-78 in encouraging the growth of cancer cells, as silencing GCL-2 had significant effects on the growth of melanoma in mice but silencing ECL-78 did not. Furthermore, senescent fibroblasts were confirmed to be the source of the harmful GCL-2, as silencing this compound in the melanoma itself had no significant effect.

The protein that drives melanoma’s growth

A more in-depth examination found this to be due to the phosphorylation of the cAMP-responsive element binding protein (CREB). CREB activation leads to tumor progression in melanoma, activating several related cancer genes, and GCL-2 was found to significantly drive this effect, with ECL-78’s effect being much weaker. Removing GCL-2 from the environment of melanoma was found to almost completely stop CREB activation, both in conditioned media and in mice.

The researchers found that significant CREB activation occurs only in the malignant part of melanoma, not the benign part. It drives glycolysis, a form of energy use that encourages cancer progression. Directly inhibiting this process, either by suppressing CREB or suppressing glycolysis in these cells, prevents the related acceleration of cancer, thus providing strong evidence that this is indeed the biological cause. An examination of naturally occurring melanomas confirmed their glycolytic nature.

As the researchers note, their data “allows several options for novel strategies for therapeutic intervention.” While fighting fibroblast senescence itself would be an ideal solution, targeting GCL-2 or its receptors offers a few potential avenues, and directly targeting CREB offers another. As targeting GCL-2 receptors is already being investigated in the context of other cancers [9], it may be that translating these drugs to melanoma is on the short-term horizon.

Yes I will donate❤️

Literature

[1] Kim, K. B., Kefford, R., Pavlick, A. C., Infante, J. R., Ribas, A., Sosman, J. A., … & Lewis, K. D. (2013). Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. Journal of Clinical Oncology, 31(4), 482-489.

[2] Gray-Schopfer, V. C., Dias, S. D. R., & Marais, R. (2005). The role of B-RAF in melanoma. Cancer and Metastasis Reviews, 24(1), 165-183.

[3] Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A. N., Damsky Jr, W. E., … & Bosenberg, M. (2009). Braf V600E cooperates with Pten loss to induce metastatic melanoma. Nature genetics, 41(5), 544-552.

[4] Breslow, A. (1970). Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Annals of surgery, 172(5), 902.

[5] Greene, V. R., Johnson, M. M., Grimm, E. A., & Ellerhorst, J. A. (2009). Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma. Journal of investigative dermatology, 129(6), 1483-1488.

[6] Kruijff, S., Bastiaannet, E., Francken, A. B., Schaapveld, M., Van Der Aa, M., & Hoekstra, H. J. (2012). Breslow thickness in the Netherlands: a population-based study of 40 880 patients comparing young and elderly patients. British journal of cancer, 107(3), 570-574.

[7] Liu, J., Zheng, R., Zhang, Y., Jia, S., He, Y., & Liu, J. (2023). The cross talk between cellular senescence and melanoma: From molecular pathogenesis to target therapies. Cancers, 15(9), 2640.

[8] Mooi, W. J., & Peeper, D. S. (2006). Oncogene-induced cell senescence—halting on the road to cancer. New England Journal of Medicine, 355(10), 1037-1046.

[9] Campbell, L. M., Maxwell, P. J., & Waugh, D. J. (2013). Rationale and means to target pro-inflammatory interleukin-8 (CXCL8) signaling in cancer. Pharmaceuticals, 6(8), 929-959.

Date Posted: November 19, 2025

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The Impact of Plant Polyphenols on Ovarian Aging

A recent review in the Journal of Ovarian Research summarizes current knowledge of the impact of various polyphenols on different aspects of ovarian aging. The researchers discuss that polyphenol supplementation could be used as an intervention to delay ovarian aging [1].

Every woman’s problem

Ovarian aging and cessation of proper ovarian functioning precede aging in other organs. Ovarian aging is related to a reduction of oocyte quality and quantity, which is the main reason for age-related infertility.

Beyond the fertility problems, ovarian aging impacts lifespan and is also linked to many age-related conditions, such as osteoporosis, cardiovascular disease, and neurodegenerative disorders. Therefore, finding ways to delay it is in the interest of every female, regardless of her childbearing goals.

At this moment, hormone replacement therapy and assisted reproductive technologies are used to address ovarian aging-related problems; however, they are unable to reverse female reproductive aging and the declining ovarian reserve. Longevity researchers are currently seeking ways to extend the female reproductive span, but before effective therapies are on the market, lifestyle factors can be utilized to address ovarian aging.

The authors of this review highlight polyphenols, naturally occurring metabolites found in fruits, vegetables, nuts, seeds, herbs, spices, and medicinal plants, as one possible intervention. Polyphenols exhibit strong biological activities, including antioxidant, anti-inflammatory, antibacterial, and antiviral properties, and demonstrate numerous beneficial effects. Studies also suggest that they can reduce the risk of cardiovascular disease and neurodegenerative disorders [2].

Delaying ovarian aging

The first part of this review discusses resveratrol, a plant-derived polyphenol that has antioxidant and anti-apoptotic properties. Multiple studies have shown that resveratrol’s dietary supplementation or oral administration ”alleviated ovarian oxidative stress damage, restored hormone levels, reduced ovarian cell apoptosis, and improved reproductive performance in animals” [3-7]. It also positively affected epigenetic changes and gene expression in the aging ovary.

Polyphenols extracted from tea leaves were shown to reduce inflammatory responses and oxidative stress and to improve ovarian reserve and ovarian function in animal models of induced ovarian damage [8, 9]. Human, mice, and other mammalian research also suggested their benefits in “alleviating ovarian aging and improving reproductive performance by enhancing oocyte quality and reducing oxidative stress” [10-12].

Quercetin was described as having strong antioxidant properties. It can promote in vitro maturation of oocytes from aged mice and humans [13] and slow down the aging of human ovarian cells [14]. Experiments in middle-aged mice also showed that oral administration improved estrous cycles, pregnancy rate, and ovarian reserve [14]. In polycystic ovary syndrome (PCOS) models, quercetin reversed many detrimental changes, such as irregular ovulation and hormone secretion, or increased ovarian cell apoptosis and inflammation [15, 16]. Similar beneficial effects were also seen in experiments in livestock and poultry animals.

Proanthocyanidins are among the most potent natural antioxidants and possess several other beneficial characteristics. They have been linked to ovarian health in multiple studies. Research in rodents and human cells reported that proanthocyanidins reduced oxidative stress, inhibited ovarian cells apoptosis, improved oocyte viability and quality, modulated hormone levels, and alleviated PCOS [17-20].

Less commonly studied polyphenols also mitigate ovarian aging. Curcumin “has been found to delay the ovarian aging process by increasing follicular number, modulating hormone secretion, reducing oxidative stress, enhancing oocyte maturation and embryo development in an aged mouse model” [21]. Other polyphenols, such as chlorogenic acid, ferulic acid, and pterostilbene, have been shown to positively impact ovarian reserve, ovarian function, and oocyte quality by mitigating oxidative stress, reducing ovarian cell apoptosis, and reducing DNA damage [22-25].

It is worth noting that several studies have shown that a moderate dose of polyphenols can make a profound difference, and high doses of polyphenols can be toxic and cause ovarian damage and impair oocyte maturation. [17, 26-29].

Many mechanisms, one goal

The beneficial effects of polyphenols can be achieved through modulations of many molecular pathways. One of them involves oxidative stress and the excessive production of reactive oxygen species (ROS), which can contribute to an increase in inflammation and disrupt the redox balance, leading to damage to mitochondrial function, telomere shortening, apoptosis, and inflammation, all of which compromise the proper functioning of ovaries and contribute to ovarian aging.

Since polyphenols have antioxidant properties, the researchers investigated their role in delaying ovarian aging by examining the effects of resveratrol, quercetin, and epigallocatechin gallate (EGCG). Those polyphenols have been shown to modulate multiple molecular signaling pathways related to oxidative stress, improve ovarian antioxidant capacity, and reduce ovarian cell apoptosis [30-32]. A human randomized controlled trial also showed a positive role of plant polyphenols (curcumin or resveratrol supplementation) in alleviating ovarian aging by reducing oxidative stress [33, 34].

Polyphenols’ anti-inflammatory properties can also help alleviate ovarian aging by reducing inflammation, which negatively impacts ovarian health. These benefits were demonstrated in animal and human models of ovarian damage [8,35]. Reduction of inflammation and improved oocyte and embryo quality resulted from polyphenol supplementation in women with PCOS who received quercetin [36]. However, there is still a need for research on the impact of polyphenols on inflammation markers in naturally aging ovaries.

Aging-related hormonal dysregulation significantly impacts ovarian aging. The hypothalamic-pituitary-ovary (HPO) axis controls hormones related to the reproductive system. Aging-related dysregulation of the HPO axis contributes to the depletion of the ovarian reserve and decreased quality and quantity of ovarian cells [37]. A growing body of research suggests that plant polyphenols regulate the sensitivity and secretion of reproductive hormones, potentially mitigating ovarian aging. The impact of polyphenols on hormonal balance and ovarian health was tested in preclinical and clinical studies of women with PCOS, showing their benefits for ovarian health through the regulation of hormone secretion [38-40].

The microenvironment surrounding the ovaries is also essential. This environment normally supports ovary and oocyte maturation, but aging leads to the accumulation of metabolites that might disrupt the homeostasis. The gut microbiota and its metabolites influence the ovarian microenvironment via the gut-ovary axis. Through this axis, the ovary communicates with the gut microbiota via hormone secretion. On the other hand, gut microbes produce metabolic signalling molecules that can impact ovarian function. Studies that used fecal microbiota transplants suggest that maintaining “a youthful gut microbiota may help preserve ovarian function and reproductive health” [41]. Similarly, experiments with laying hens as a model suggested that polyphenol supplementation could improve ovarian function by modulating the gut microbiota [27, 42].

There appear to be many mechanisms and pathways through which polyphenols impact ovarian aging. This is unsurprising since polyphenols are a broad group of molecules with diverse chemical structures, resulting in distinct bioactivity profiles.

This knowledge can be used to design safe plant polyphenol-based interventions for female reproductive longevity that can be used alone or in combination with other treatments.

Yes I will donate❤️

Literature

[1] Gong, H., Zhang, H., Liu, Y., Mao, X., & Wang, J. (2025). Role and mechanisms of plant polyphenols in ovarian aging. Journal of ovarian research, 18(1), 239.

[2] Potì, F., Santi, D., Spaggiari, G., Zimetti, F., & Zanotti, I. (2019). Polyphenol Health Effects on Cardiovascular and Neurodegenerative Disorders: A Review and Meta-Analysis. International journal of molecular sciences, 20(2), 351.

[3] Yong, W., Jiao, J., Kou, Z., Wang, C., & Pang, W. (2021). Resveratrol ameliorates malathion-induced estrus cycle disorder through attenuating the ovarian tissue oxidative stress, autophagy and apoptosis. Reproductive toxicology (Elmsford, N.Y.), 104, 8–15.

[4] Okamoto, N., Sato, Y., Kawagoe, Y., Shimizu, T., & Kawamura, K. (2022). Short-term resveratrol treatment restored the quality of oocytes in aging mice. Aging, 14(14), 5628–5640.

[5] Wu, H., Xue, J., Di, H., Lv, C., Hao, Y., & Nie, Z. (2022). Resveratrol improves ovarian function in aged rat by inhibiting oxidative stress and activating the Sirt1. General physiology and biophysics, 41(1), 53–61.

[6] Herrero, Y., Velázquez, C., Pascuali, N., May, M., Abramovich, D., Scotti, L., & Parborell, F. (2023). Resveratrol alleviates doxorubicin-induced damage in mice ovary. Chemico-biological interactions, 376, 110431.

[7] Zhu, H., Li, X., Qiao, M., Sun, X., & Li, G. (2023). Resveratrol Alleviates Inflammation and ER Stress Through SIRT1/NRF2 to Delay Ovarian Aging in a Short-Lived Fish. The journals of gerontology. Series A, Biological sciences and medical sciences, 78(4), 596–602.

[8] Fabbri, R., Macciocca, M., Vicenti, R., Caprara, G., Piccinni, M. P., Paradisi, R., Terzano, P., Papi, A., & Seracchioli, R. (2019). Epigallocatechin-3-gallate inhibits doxorubicin-induced inflammation on human ovarian tissue. Bioscience reports, 39(5), BSR20181424.

[9] Chen, Q., Xu, Z., Li, X., Du, D., Wu, T., Zhou, S., Yan, W., Wu, M., Jin, Y., Zhang, J., & Wang, S. (2021). Epigallocatechin gallate and theaflavins independently alleviate cyclophosphamide-induced ovarian damage by inhibiting the overactivation of primordial follicles and follicular atresia. Phytomedicine : international journal of phytotherapy and phytopharmacology, 92, 153752.

[10] Zhang, H., Su, W., Zhao, R., Li, M., Zhao, S., Chen, Z. J., & Zhao, H. (2024). Epigallocatechin-3-gallate improves the quality of maternally aged oocytes. Cell proliferation, 57(4), e13575.

[11] Fan, Z., Xiao, Y., Chen, Y., Wu, X., Zhang, G., Wang, Q., & Xie, C. (2015). Effects of catechins on litter size, reproductive performance and antioxidative status in gestating sows. Animal nutrition (Zhongguo xu mu shou yi xue hui), 1(4), 271–275.

[12] Zhou, C., Zhang, X., ShiYang, X., Wang, H., & Xiong, B. (2019). Tea polyphenol protects against cisplatin-induced meiotic defects in porcine oocytes. Aging, 11(13), 4706–4719.

[13] Cao, Y., Zhao, H., Wang, Z., Zhang, C., Bian, Y., Liu, X., Zhang, C., Zhang, X., & Zhao, Y. (2020). Quercetin promotes in vitro maturation of oocytes from humans and aged mice. Cell death & disease, 11(11), 965.

[14] Wu, M., Tang, W., Chen, Y., Xue, L., Dai, J., Li, Y., Zhu, X., Wu, C., Xiong, J., Zhang, J., Wu, T., Zhou, S., Chen, D., Sun, C., Yu, J., Li, H., Guo, Y., Huang, Y., Zhu, Q., Wei, S., … Wang, S. (2024). Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1. Nature aging, 4(4), 527–545.

[15] Jiao, Y., Wang, Y., Jiang, T., Wen, K., Cong, P., Chen, Y., & He, Z. (2022). Quercetin protects porcine oocytes from in vitro aging by reducing oxidative stress and maintaining the mitochondrial functions. Frontiers in cell and developmental biology, 10, 915898.

[16] Shah, M. Z. U. H., Shrivastva, V. K., Mir, M. A., Sheikh, W. M., Ganie, M. A., Rather, G. A., Shafi, M., Bashir, S. M., Ansari, M. A., Al-Jafary, M. A., Al-Qhtani, M. H., Homeida, A. M., & Al-Suhaimi, E. A. (2023). Effect of quercetin on steroidogenesis and folliculogenesis in ovary of mice with experimentally-induced polycystic ovarian syndrome. Frontiers in endocrinology, 14, 1153289.

[17] Barbe, A., Ramé, C., Mellouk, N., Estienne, A., Bongrani, A., Brossaud, A., Riva, A., Guérif, F., Froment, P., & Dupont, J. (2019). Effects of Grape Seed Extract and Proanthocyanidin B2 on In Vitro Proliferation, Viability, Steroidogenesis, Oxidative Stress, and Cell Signaling in Human Granulosa Cells. International journal of molecular sciences, 20(17), 4215.

[18] Luo, Y., Zhuan, Q., Li, J., Du, X., Huang, Z., Hou, Y., & Fu, X. (2020). Procyanidin B2 Improves Oocyte Maturation and Subsequent Development in Type 1 Diabetic Mice by Promoting Mitochondrial Function. Reproductive sciences (Thousand Oaks, Calif.), 27(12), 2211–2222.

[19] Zhou, Y., Lan, H., Dong, Z., Cao, W., Zeng, Z., & Song, J. L. (2021). Dietary proanthocyanidins alleviated ovarian fibrosis in letrozole-induced polycystic ovary syndrome in rats. Journal of food biochemistry, 45(5), e13723.

[20] Zhou, S., Zhao, A., Wu, Y., Mi, Y., & Zhang, C. (2022). Protective Effect of Grape Seed Proanthocyanidins on Oxidative Damage of Chicken Follicular Granulosa Cells by Inhibiting FoxO1-Mediated Autophagy. Frontiers in cell and developmental biology, 10, 762228.

[21] Azami, S. H., Nazarian, H., Abdollahifar, M. A., Eini, F., Farsani, M. A., & Novin, M. G. (2020). The antioxidant curcumin postpones ovarian aging in young and middle-aged mice. Reproduction, fertility, and development, 32(3), 292–303.

[22] Yin, Y. J., Zhang, Y. H., Wang, Y., Jiang, H., Zhang, J. B., Liang, S., & Yuan, B. (2023). Ferulic acid ameliorates the quality of in vitro-aged bovine oocytes by suppressing oxidative stress and apoptosis. Aging, 15(21), 12497–12512.

[23] Qian, F., Zhu, Z., Luo, C., Qi, R., Wei, L., Bo, L., Jiang, W., & Mao, C. (2025). Chlorogenic Acid Ameliorates Chronic Unpredictable Stress-Induced Diminished Ovarian Reserve Through Ovarian Renin-Angiotensin System. Molecular nutrition & food research, 69(5), e202400814.

[24] Chu, Y., Zhao, J., Zhao, Y., Li, Z., Yang, S., Chen, N., Liu, Y., Zhang, J., Zhou, L., & Chen, X. (2025). Multi-Omics Reveal the Effects and Regulatory Mechanism of Dietary Magnolol Supplementation on Production Performance of Post-Peak Laying Hens. Journal of agricultural and food chemistry, 73(7), 4027–4041.

[25] Chen, F., Zhang, H., Du, E., Jin, F., Zheng, C., Fan, Q., Zhao, N., Guo, W., Zhang, W., Huang, S., & Wei, J. (2021). Effects of magnolol on egg production, egg quality, antioxidant capacity, and intestinal health of laying hens in the late phase of the laying cycle. Poultry science, 100(2), 835–843.

[26] Gao, W., Jin, Y., Hao, J., Huang, S., Wang, D., Quan, F., Ren, W., Zhang, J., Zhang, M., & Yu, X. (2021). Procyanidin B1 promotes in vitro maturation of pig oocytes by reducing oxidative stress. Molecular reproduction and development, 88(1), 55–66.

[27] Moreira-Pinto, B., Costa, L., Felgueira, E., Fonseca, B. M., & Rebelo, I. (2021). Low Doses of Resveratrol Protect Human Granulosa Cells from Induced-Oxidative Stress. Antioxidants (Basel, Switzerland), 10(4), 561.

[28] Liang, Y., Xu, M. L., Gao, X., Wang, Y., Zhang, L. N., Li, Y. C., & Guo, Q. (2023). Resveratrol improves ovarian state by inhibiting apoptosis of granulosa cells. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 39(1), 2181652.

[29] Huang, Z., Pang, Y., Hao, H., Du, W., Zhao, X., & Zhu, H. (2018). Effects of epigallocatechin-3-gallate on bovine oocytes matured in vitro. Asian-Australasian journal of animal sciences, 31(9), 1420–1430.

[30] Li, N., & Liu, L. (2018). Mechanism of resveratrol in improving ovarian function in a rat model of premature ovarian insufficiency. The journal of obstetrics and gynaecology research, 44(8), 1431–1438.

[31] Yan, Z., Dai, Y., Fu, H., Zheng, Y., Bao, D., Yin, Y., Chen, Q., Nie, X., Hao, Q., Hou, D., & Cui, Y. (2018). Curcumin exerts a protective effect against premature ovarian failure in mice. Journal of molecular endocrinology, 60(3), 261–271.

[32] Barberino, R. S., Santos, J. M. S., Lins, T. L. B. G., Menezes, V. G., Monte, A. P. O., Gouveia, B. B., Palheta, R. C., Jr, & Matos, M. H. T. (2020). Epigallocatechin-3-gallate (EGCG) reduces apoptosis of preantral follicles through the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway after in vitro culture of sheep ovarian tissue. Theriogenology, 155, 25–32.

[33] Heshmati, J., Moini, A., Sepidarkish, M., Morvaridzadeh, M., Salehi, M., Palmowski, A., Mojtahedi, M. F., & Shidfar, F. (2021). Effects of curcumin supplementation on blood glucose, insulin resistance and androgens in patients with polycystic ovary syndrome: A randomized double-blind placebo-controlled clinical trial. Phytomedicine : international journal of phytotherapy and phytopharmacology, 80, 153395.

[34] Ardehjani, N. A., Agha-Hosseini, M., Nashtaei, M. S., Khodarahmian, M., Shabani, M., Jabarpour, M., Fereidouni, F., Rastegar, T., & Amidi, F. (2024). Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial. Journal of ovarian research, 17(1), 143.

[35] Ardehjani, N. A., Agha-Hosseini, M., Nashtaei, M. S., Khodarahmian, M., Shabani, M., Jabarpour, M., Fereidouni, F., Rastegar, T., & Amidi, F. (2024). Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial. Journal of ovarian research, 17(1), 143.

[36] Vaez, S., Parivr, K., Amidi, F., Rudbari, N. H., Moini, A., & Amini, N. (2023). Quercetin and polycystic ovary syndrome; inflammation, hormonal parameters and pregnancy outcome: A randomized clinical trial. American journal of reproductive immunology (New York, N.Y. : 1989), 89(3), e13644.

[37] Wu, C., Chen, D., Stout, M. B., Wu, M., & Wang, S. (2025). Hallmarks of ovarian aging. Trends in endocrinology and metabolism: TEM, 36(5), 418–439.

[38] Hu, H., Zhang, J., Xin, X., Jin, Y., Zhu, Y., Zhang, H., Fan, R., Ye, Y., & Li, D. (2024). Efficacy of natural products on premature ovarian failure: a systematic review and meta-analysis of preclinical studies. Journal of ovarian research, 17(1), 46.

[39] Ali Fadlalmola, H., Elhusein, A. M., Al-Sayaghi, K. M., Albadrani, M. S., Swamy, D. V., Mamanao, D. M., El-Amin, E. I., Ibrahim, S. E., & Abbas, S. M. (2023). Efficacy of resveratrol in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials. The Pan African medical journal, 44, 134.

[40] Malik, S., Saeed, S., Saleem, A., Khan, M. I., Khan, A., & Akhtar, M. F. (2024). Alternative treatment of polycystic ovary syndrome: pre-clinical and clinical basis for using plant-based drugs. Frontiers in endocrinology, 14, 1294406.

[41] Xu, L., Zhang, Q., Dou, X., Wang, Y., Wang, J., Zhou, Y., Liu, X., & Li, J. (2022). Fecal microbiota transplantation from young donor mice improves ovarian function in aged mice. Journal of genetics and genomics = Yi chuan xue bao, 49(11), 1042–1052.

[42] Zhang, T., Bai, S., Ding, X., Zeng, Q., Xuan, Y., Xu, S., Mao, X., Peng, H., Zhang, K., & Wang, J. (2024). Pu-erh tea theabrownin improves the ovarian function and gut microbiota in laying hens. Poultry science, 103(7), 103795.

Date Posted: November 18, 2025

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Vincere Biosciences Awarded $5 Million Grant

Cambridge, MA, USA – November 18, 2025: Vincere Biosciences today announced the receipt of a $5 million grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) through its Therapeutics Pipeline Program, which supports the advancement of promising therapies through preclinical and clinical stages. The initiative focuses on candidates with strong potential to slow or halt disease progression or alleviate burdensome symptoms for those living with Parkinson’s disease. The funding accelerates Vincere’s lead USP30 inhibitor, a potentially first-in-class therapeutic designed to modify the course of Parkinson’s disease, through IND-enabling studies toward a 2026 clinical trial initiation. In parallel, the grant will also fund Vincere’s biomarker development efforts to evaluate target engagement and guide clinical translation, strengthening the foundation for future human studies.

“The Michael J. Fox Foundation remains steadfast in our mission to accelerate the development of transformative treatments and, ultimately, a cure for Parkinson’s disease,” said Jessica Tome Garcia, PhD, MJFF’s lead scientific program manager. “Our collaboration with Vincere Biosciences over the years has supported the advancement of research targeting mitochondrial dysfunction, a key driver of Parkinson’s pathology. This next phase of work builds on that foundation and represents important progress toward disease-modifying therapies that could meaningfully improve patients’ lives.”

Targeting the Root Cause of Neuronal Vulnerability

Mitochondrial dysfunction and impaired mitophagy are central features of PD pathophysiology. Mitophagy, the selective recycling of damaged mitochondria, is essential for maintaining neuronal health. In PD, this process is often compromised, leading to toxic buildup of defective mitochondria that accelerates neurodegeneration. Vincere aims to restore mitochondrial quality control and prevent the progression of neuronal injury by selectively inhibiting USP30, a mitochondrial deubiquitinating enzyme that acts as a negative regulator of mitophagy. By targeting the cellular processes at the root of Parkinson’s, Vincere’s approach has the potential to not only slow disease progression but also improve quality of life for millions living with PD.

“Mitochondria sit at the crossroads of Parkinson’s and aging (the biggest risk factor for Parkinson’s),” says Dr. Spring Behrouz, co-founder and CEO of Vincere, “fix the mitochondria and you strike at the root of the disease. MJFF’s support helps us move that science from the lab to the clinic.”

Transitioning from Discovery to Clinic

MJFF’s award will fund critical IND-enabling studies, including pharmacology, toxicology, and regulatory workstreams. These studies will establish the foundation required for a successful Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA), marking the transition of Vincere’s program from preclinical development to the clinic. This award builds on prior MJFF support, which continues to move Vincere’s USP30 inhibitor program forward.

“It’s been exciting to see growing enthusiasm for USP30 since our AI platform prioritized this target in 2018. The new support from MJFF positions the company well for ongoing partnering discussions with larger organizations who may accelerate clinical development of this promising approach,” says Andy Lee, co-founder and CBO of Vincere.

About Vincere Biosciences Inc.

https://www.vincerebio.com

Boston-based Vincere Biosciences develops innovative, mechanism-driven therapeutics that target the intersection of aging and disease. Using proprietary computational tools and cutting-edge biology, Vincere is dedicated to discovering and developing small molecules that address the root causes of conditions like Parkinson’s and other age-related disorders.

Yes I will donate❤️

Date Posted: November 18, 2025

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Improved Stem Cells Rejuvenate the Brains of Monkeys

Scientists have genetically modified human mesenchymal progenitor cells to express a more potent version of the “longevity gene” FOXO3, producing rejuvenative effects in monkeys, mice, and human cells [1].

Making aging-resistant cells

Stem cell exhaustion is one of the mechanisms of aging. Replenishing the aging stem cell pool with new exogenous cells sounds like a good idea, but when new cells interact with an aging organism, they often experience accelerated aging and senescence [2]. To overcome this problem, in a new study published in Cell, scientists from China created genetically modified stem cells and injected them into cynomolgus monkeys.

The team started with wild-type human mesenchymal progenitor cells (MPCs), stem cells that can differentiate into several cell types and have a low immunogenic risk: they express few surface proteins that can be recognized by the immune system and secrete factors that actually calm immunity around them.

The MPCs were differentiated from human embryonic stem cells modified by a CRISPR-based editing system, which tweaked FOXO3, a transcription factor that orchestrates stress resistance and repair. FOXO3 is considered a promising “longevity gene,” since it extends lifespan and healthspan in animal models [3] and is associated with human longevity [4]. In stem cells, FOXO3 helps keep stem cells quiescent but competent, and it modulates inflammatory signaling.

In more technical terms, the researchers replaced two serine residues (Ser253 and Ser315) with alanine, eliminating the ability of these sites to be phosphorylated. Because phosphorylation at these sites normally promotes FOXO3 nuclear export and inactivation, this mutation keeps FOXO3 active for longer.

In vitro, the researchers confirmed that their senescence-resistant MPCs (SRCs) had a more youthful phenotype than wild-type MPCs (WTCs), exhibiting lower senescence and inflammation markers (SA-β-gal, IL-6, IL-8), longer telomeres, and more stable heterochromatin. SRCs were more competent at differentiation and more resistant to stressors, and they had their proliferation and tumor-suppressor programs upregulated.

Significant effects on monkeys

In the main experiment, cynomolgus monkeys were divided into four age groups. The three younger groups were used for studying natural aging in these animals and creating several bespoke clocks, which combined gene expression and DNA methylation patterns across multiple tissues to estimate each animal’s biological age. The last and oldest group (19-23 years) formed the intervention cohort and was further divided into subgroups that received a sham treatment, human WTCs, or human SRCs.

The treatment groups received bi-weekly IV infusions for 44 weeks, and upon the completion of the treatment, a large battery of tests was performed. The first part of it focused on the brain. Functionally, on a delayed-reward memory task, the SRC group performed significantly better than old controls, while the WTC group’s results were not clearly distinguishable from this control group’s.

SRCs preserved or even partially restored cortical thickness and volume in several brain regions, relative to age-matched controls. WTCs had weaker effects. Diffusion MRI revealed improved structural connectivity.

SRCs also reduced age-related myelin thinning and the levels of amyloid-β aggregates and p-Tau aggregates, both of which indicate Alzheimer’s disease. A single-cell clock showed an average reduction of biological age by about 2.5 years across hippocampal cell types following the SRC treatment.

This and other biological age measurements were compared to similarly aged untreated monkeys rather than the animals’ own baselines. In other words, the net age reversal, as measured by these metrics, was approximately 0.9 years less, as this is how long the experiment took to conduct.

The researchers also profiled 13 immune cell types. SRCs reversed more aging-related changes in gene expression than WTCs. Both treatments downregulated cellular senescence and apoptosis while upregulating DNA damage repair, autophagy, and lymphocyte differentiation and function. Both treatments also reduced the inflammation markers IL-6 and TNF-α in the plasma and CHIT1, a marker of microglial activation and neuroinflammation, in the cerebrospinal fluid (CSF).

Exosomes recapitulate many of the changes

In total, the team applied their bulk-tissue RNA-seq-based clock to 61 tissues from 10 organ systems. Generally, both WTCs and SRCs attenuated age-related trajectories, but SRCs had larger effects in most tissues, with an average biological age reduction of 3.3 years by SRCs compared to 2.8 years by WTCs.

Interestingly, the strongest effects were observed in reproductive tissues (ovary, testis, uterus, prostate, seminal vesicle, and epididymis). In tissues where transcriptomic aging was reversed, the methylation-based clock agreed with the transcriptomic one: according to it, SRCs made brains 5 years younger and skeletal muscle 4 years younger on average.

Because MPCs are thought to act largely via secreted factors, the researchers zoomed in on exosomes. Both in mice and in human cells, SRC-derived exosomes produced significant rejuvenation, lowering senescence markers and shifting gene expression profiles towards younger phenotypes.

Yes I will donate❤️

Literature

[1] Lei, J., Xin, Z., Liu, N., Ning, T., Jing, Y., Qiao, Y., … & Liu, G. H. (2025). Senescence-resistant human mesenchymal progenitor cells counter aging in primates. Cell.

[2] Liu, J., Gao, J., Liang, Z., Gao, C., Niu, Q., Wu, F., & Zhang, L. (2022). Mesenchymal stem cells and their microenvironment. Stem cell research & therapy, 13(1), 429.

[3] Flachsbart, F., Dose, J., Gentschew, L., Geismann, C., Caliebe, A., Knecht, C., … & Nebel, A. (2017). Identification and characterization of two functional variants in the human longevity gene FOXO3. Nature communications, 8(1), 2063.

[4] Willcox, B. J., Donlon, T. A., He, Q., Chen, R., Grove, J. S., Yano, K., … & Curb, J. D. (2008). FOXO3A genotype is strongly associated with human longevity. Proceedings of the National Academy of Sciences, 105(37), 13987-13992.

Date Posted: November 17, 2025

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A Sarcopenia-Related MicroRNA May Help Pinpoint Its Origin

In Aging Cell, researchers have discovered a potential way to use a microRNA to diagnose sarcopenia, the age-related loss of muscle.

Primary and secondary sarcopenia

Previous research has been able to distinguish sarcopenia by its sources. Primary sarcopenia directly comes from the processes of aging, while secondary sarcopenia is a side effect of such things as poor nutrition, atrophy from disuse, and both acute and chronic diseases [1]. The researchers of this study note that the difference is difficult to distinguish in the clinic, where these two categories heavily overlap.

Heart failure, which is defined here as a progressive clinical syndrome [2] rather than an effect of acute causes such as heart attack, is heavily associated with sarcopenia [3]. A substantial amount of other work has shone some light on this relationship, and these problems share many of the same causes [4].

Looking for a way to diagnose the true causes of sarcopenia in the context of heart failure, these researchers have turned to microRNAs, non-coding RNA molecules that affect gene transcription and have been used to investigate the sources of diseases, including sarcopenia in the context of obesity [5]. One of these microRNAs is microRNA-22-3p (miR-22), which is found in many species and is expressed predominantly in muscle tissue and nerves [6]. This suggests a possible use in diagnostics and therapies, and work has been done in using it as a treatment for heart attack [7].

The biological effects of miR-22 vary by tissue. Some work has found that it blocks calcium uptake in a way that leads to diminished heart contraction ability [8]. Other work has found that it suppresses proliferation while encouraging differentiation in skeletal muscle cells, and inhibiting it does the opposite [9]. Work in mice has revealed that miR-22 in exosomes, which cells use to send signals to one another, leads to insulin resistance [10]. These researchers also performed their own in silico pathway analysis, which confirmed that it impacts an enormous network of metabolic and age-related pathways, many of which are related to aging.

Two studies create a combined picture

These researchers evaluated data from the SPRINTT study, which recruited 61 people aged 70 or older. Half of the participants showed signs of sarcopenia, which SPRINTT defined as a pre-disability state defined by gradual muscle failure and measured using a significant absence of lean mass. People with advanced heart conditions and other serious age-related disorders, such as cancer and dementia, were excluded. While that study focused on technological and nutritional interventions rather than microRNAs, it still took biomarker data from its participants. SPRINTT was intended to evaluate people with primary sarcopenia.

Other data came from SICA-HF, which recruited 176 people with heart failure of all ages. Like SPRINTT, its basis for a sarcopenia diagnosis was the absence of sufficient muscle mass. The reearchers used SICA-HF as their basis for secondary sarcopenia.

Using data from the SPRINTT study, the researchers found that people with primary sarcopenia have significantly more miR-22 than people without it. This difference was not found in other microRNAs that the researchers analyzed. Using this data, they determined that it was possible to develop a miR-22-based test that could be used to screen for sarcopenia, although such a test would not be completely perfect.

Interestingly, however, the opposite was true for secondary sarcopenia, with people with sarcopenia in the SICA-HF study being more likely to have less miR-22. While this data was somewhat weaker than the results derived from SPRINTT, it still reached the level of statistical significance.

The combination of these results leads these researchers to believe that miR-22 is a potentially useful diagnostic tool for the evaluation of primary versus secondary sarcopenia. They offer a few plausible reasons why this may be the case, suggesting that the source of the circulating miR-22 (cardiac or skeletal muscle) may be the primary difference [11] and that miR-22 may play different roles in these muscle types. The researchers also suggest that the effects of miR-22 on differentiation and proliferation, leading to changes in its regulation, may be involved. Furthermore, the correlation between miR-22 and sarcopenia in the cardiac patients may be due to an upstream cause rather than a direct relationship.

These researchers further acknowledge that there are limitations in using two separate studies to create a conclusion based on both of them. Those studies did not define sarcopenia in exactly the same way, and there is still the issue of overlapping causes. Therefore, substantial further work must be done in order to determine how microRNAs relate to this muscle-wasting condition.

Yes I will donate❤️

Literature

[1] Cruz-Jentoft, A. J., Bahat, G., Bauer, J., Boirie, Y., Bruyère, O., Cederholm, T., … & Zamboni, M. (2019). Sarcopenia: revised European consensus on definition and diagnosis. Age and ageing, 48(1), 16-31.

[2] Tomasoni, D., Adamo, M., Lombardi, C. M., & Metra, M. (2019). Highlights in heart failure. ESC heart failure, 6(6), 1105-1127.

[3] Fülster, S., Tacke, M., Sandek, A., Ebner, N., Tschöpe, C., Doehner, W., … & von Haehling, S. (2013). Muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF). European heart journal, 34(7), 512-519.

[4] Sato, R., Vatic, M., Peixoto da Fonseca, G. W., Anker, S. D., & von Haehling, S. (2024). Biological basis and treatment of frailty and sarcopenia. Cardiovascular research, 120(9), 982-998.

[5] Dowling, L., Duseja, A., Vilaca, T., Walsh, J. S., & Goljanek‐Whysall, K. (2022). MicroRNAs in obesity, sarcopenia, and commonalities for sarcopenic obesity: a systematic review. Journal of Cachexia, Sarcopenia and Muscle, 13(1), 68-85.

[6] Huang, Z. P., & Wang, D. Z. (2018). miR-22 in smooth muscle cells: a potential therapy for cardiovascular disease. Circulation, 137(17), 1842-1845.

[7] Gupta, S. K., Foinquinos, A., Thum, S., Remke, J., Zimmer, K., Bauters, C., … & Thum, T. (2016). Preclinical development of a microRNA-based therapy for elderly patients with myocardial infarction. Journal of the American College of Cardiology, 68(14), 1557-1571.

[8] Gurha, P., Wang, T., Larimore, A. H., Sassi, Y., Abreu-Goodger, C., Ramirez, M. O., … & Rodriguez, A. (2013). microRNA-22 promotes heart failure through coordinate suppression of PPAR/ERR-nuclear hormone receptor transcription. PLoS One, 8(9), e75882.

[9] Wang, S., Cao, X., Ge, L., Gu, Y., Lv, X., Getachew, T., … & Sun, W. (2022). MiR-22-3p inhibits proliferation and promotes differentiation of skeletal muscle cells by targeting IGFBP3 in Hu sheep. Animals, 12(1), 114.

[10] Zhang, H., Zhang, X., Wang, S., Zheng, L., Guo, H., Ren, Y., … & Yan, Y. (2023). Adipocyte-derived exosomal miR-22-3p modulated by circadian rhythm disruption regulates insulin sensitivity in skeletal muscle cells. Journal of Biological Chemistry, 299(12).

Date Posted: November 14, 2025

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NAD+ Rescues Mouse Tauopathy by Fixing Alternative Splicing

A new study reveals a surprising mechanism that might be behind the beneficial effects of NAD+ in preclinical models of Alzheimer’s [1].

Which way to splice it?

Not every part of a DNA sequence gets translated into a protein. Each sequence consists of exons, which are included in the final RNA transcript, and introns, which are thrown away.

However, nothing is that simple in biology. Exons and introns can be combined in various ways to create several versions of the protein, with different and sometimes opposite qualities. This is known as alternative RNA splicing. It gets increasingly dysregulated as we age [2] and has been implicated in various diseases, including Alzheimer’s disease (AD) [3].

NAD+ is a key metabolite that also modulates RNA processing. It slows Alzheimer’s disease progression in preclinical models [4], but the mechanism behind this effect is not well understood. In a new study from the University of Oslo published in Science Advances, the researchers asked whether this could be related to alternative splicing.

“Preliminary studies have shown that supplementation with NAD⁺ precursors, such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), can offer therapeutic benefits in AD animal models and early clinical trials. However, the molecular mechanisms behind these benefits remain largely unclear,” first author Alice Ruixue Ai said.

From worms to mice

First, the researchers used C. elegans nematode worms engineered with two key features: neurons that express a human P301L tau variant (a model of tauopathy, which is a hallmark of Alzheimer’s) and a fluorescent reporter that changes green/red signal depending on how a particular exon is spliced. In aging tau worms, the reporter showed that splicing becomes gradually more error-prone. The worms also developed memory-like defects and shorter lifespans.

Treating worms from hatching with nicotinamide riboside (NR), a NAD+ precursor, altered the neuronal splicing fidelity, with strong effects early in life, suggesting that NAD+ can modulate splicing machinery during development. It also partially rescued lifespan and memory.

In a mouse model of tauopathy (Tau.P301S mice, with human P301S tau expressed in neurons), the researchers saw a similar picture: splicing in tau mice was disrupted and partially normalized by NR. This time, however, they focused on the mechanism.

Hippocampal RNA sequencing found 509 differentially expressed genes compared to wild-type mice, with many affected genes involved in RNA processing and splicing. The gene Eva1c, which codes for a protein involved in neuronal development and activity, was both significantly upregulated and abnormally spliced in tauopathic mice compared to controls.

NR supplementation significantly reversed both expression and splicing changes, which made Eva1c stand out. An AI-based analysis suggested that the key effects were less caused by the overall levels of this protein and more by the proportions of its various isoforms.

The researchers then manipulated the gene in mice and its homolog (eva-1) in worms. In C. elegans, eva-1 knockdown abolishes NR’s benefits on lifespan and memory-like behavior in tau worms, showing that those benefits indeed were eva-1-dependent.

Restoring the balance

In a slightly different mouse model with tauopathy induced by AAV-based tau overexpression, experiments involved Eva1c manipulation alongside supplementation with NMN, another NAD+ precursor. The researchers changed the Eva1c isoform mix by overexpressing the one isoform that was most robustly altered by NR in previous experiments.

Tau.P301S AAV mice showed memory deficits in the novel object recognition test, but NMN treatment brought the readouts back to control levels. This effect disappeared with the Eva1c knockdown. Overexpressing the most NR-responsive isoform partly mimicked the NMN effect.

A similar pattern was seen for total and phosphorylated tau levels. Together, this shows that NMN’s anti-tau and pro-memory effects in this mouse model require intact Eva1c and can be mimicked by restoring the Eva1c isoform balance, such as by rescuing alternative splicing.

“Notably, we found that when the EVA1C gene was knocked down, these benefits were lost, confirming that EVA1C is essential for NAD⁺-mediated neuroprotection,” Associate Professor Evandro Fei Fang-Stavem said.

Finally, mining an extensive RNA-seq dataset of Alzheimer’s and non-Alzheimer’s hippocampal tissue and analyzing post-mortem samples, the researchers found that EVA1C expression is altered in Alzheimer’s brains compared with controls, consistent with EVA1C being involved in human tau pathology as well.

“We propose that maintaining NAD⁺ levels could help preserve neuronal identity and delay cognitive decline, paving the way for combination treatments to enhance RNA splicing,” Ai said.

Yes I will donate❤️

Literature

[1] Ai, R., Mao, L., Jin, X., Campos-Marques, C., Zhang, S. Q., Pan, J., … & Fang, E. F. (2025). NAD+ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C. Science Advances, 11(45), eady9811.

[2] Bhadra, M., Howell, P., Dutta, S., Heintz, C., & Mair, W. B. (2020). Alternative splicing in aging and longevity. Human genetics, 139(3), 357-369.

[3] Nikom, D., & Zheng, S. (2023). Alternative splicing in neurodegenerative disease and the promise of RNA therapies. Nature Reviews Neuroscience, 24(8), 457-473.

[4] Hou, Y., Lautrup, S., Cordonnier, S., Wang, Y., Croteau, D. L., Zavala, E., … & Bohr, V. A. (2018). NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proceedings of the National Academy of Sciences, 115(8), E1876-E1885.

Date Posted: November 13, 2025

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The Key Questions of Longevity Research

In GeroScience, a large team of researchers, including João Pedro de Magalhães, has described a hundred currently unsolved problems in the field.

Finding the right questions

Understanding the fundamental nature of aging has been a problem since people first endeavored to live longer, to the point that finding the right questions can matter more than finding the right answers. Nearly fifty years ago, B.L. Strehler attempted to tackle this in Time, Cells, and Aging [1], and there has been skepticism as to whether it can be done at all [2]. As the field has completely changed between now and Strehler’s time, these researchers chose to revisit the topic, using modern analysis techniques the most frequently asked questions in research.

These questions came from a few sources. First, they sought comments from the research community, collecting a total of 160 open problems and adding them to their database. Additionally, they held a 3-day workshop with 24 scientists in order to gain a better view of the field, creating groups and brainstorming unsolved problems, gaining another 130.

Then, the researchers filtered these problems for similarity and relevance, reducing the number to 204. They quested for how frequently these problems were mentioned in article abstracts, using a natural language processing algorithm and multiple checks to ensure that the articles and problems matched. Of these 204 problems, 100 were selected by Prof. de Magalhães for inclusion into the OpenLongevity database.

The biggest question is why

Unsurpisingly, the biggest overall question is “Why do we age?”, with 10,808 scientific articles asking this question. This was followed by a question about somatic mutation accumulation, which had 5,977. Questions about cellular processes and species longevity followed, as were questions involving fundamental aging processes in animals and whether or not those processes translate to humans. Biomarkers were also major aspects of concern. A broad question about interventions involving cellular function was less commonly asked than questions about these fundamental questions of aging.

Intervention-related questions, however, were the most commonly found on the list. These questions involved targeting inflammation, utilizing embryogenetic processes to slow aging, and employing partial reprogramming techniques. Many other questions involved the amount of overall damage that originates from particular aspects of aging, such as the secretions of senescent cells.

There were also questions that were almost never asked, mostly involving very little-researched, very particular aspects of the field. For example, only one paper asked about the homeodynamic space, which refers to organizational stability. Only a few papers asked about prioritizing interventions, and mitochondrial citrate and immune responses to mutated cells were also lightly explored topics.

The field has come a long way, but there is still much to do

There are similarities between the questions of today and the questions asked by Strehler in 1977, although he focused more on central nervous system disorders and some questions regarding inter-species differences have been fairly well resolved. Modern research is still exploring the roles of mitochondria, although the modern focus is more on such cellular dynamics than on the fundamental aspects of biology, such as enzymes and ribosomes, that were of scientific interest at the time and are largely well-understood today. However, how these biological components are changed during aging is not always certain.

Answering questions in science, especially the sorts of complex questions involved in biology, often leads to more questions. These 100 questions are intended to be fundamental to the field, and while answering them may lead to more questions, the process may lead to interventions that extend healthy human lifespan.

Yes I will donate❤️

Literature

[1] Strehler, B. (1977). Some unexplored avenues of cellular aging—current and future research. Time, Cells and Aging, edited by Strehler, B, 374-418.

[2] Partridge, L. (2010). The new biology of ageing. Philosophical Transactions of the Royal Society B: Biological Sciences, 365(1537), 147-154.

Date Posted: November 12, 2025

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If Death Were Optional, Would You Still Choose It?

The idea of living longer, healthier lives thanks to rejuvenation biotechnology has steadily become more common. Gradually increasing numbers of articles are discussing this idea, especially as science is starting to catch up and may eventually even deliver on it.

With that in mind, I was pleasantly surprised this week to be greeted by an interesting questionnaire from YouGovChat. YouGov PLC is an international, Internet-based market research and data analytics firm that has a headquarters in the UK.

Public sentiment on living forever or at least indefinitely

The question that caught my attention was: “If you could live forever, staying healthy and young, would you do it?”

The important part here is that this question includes the words healthy and young. Previous surveys have often asked this question without those important words, and that changes the response.

People don’t generally want to live longer if that additional time means being sick and frail. Simply asking people if they want to live another 20+ years often conjures up images of being in a care home. They think of having no independence or quality of life accompanying those extra years.

This is understandable. The modern healthcare system has done well in keeping people alive longer, but often without an accompanying quality of life. The idea of effectively losing what makes life worth living and prolonging suffering isn’t something desirable.

However, phrasing the question with such qualifiers can lead to a more accurate and honest answer. So, how did people respond when the question was framed with the understanding that health and youthfulness are included?

The key thing to note here is that most people in the poll were open to living long and healthy lives. However, they wanted the choice to end their life if they so desired.

In my decade as a rejuvenation biotech journalist, I have heard many reasons not to develop the technology. One of those objections is that people will be forced to take therapies and made to live longer or even indefinitely against their will.

Some of that concern may be playing into the responses here. People are likely to prefer to have such an option than not, and no one likes the idea of having no choice. We cannot truly know why people responded this way, as it was beyond the scope of the poll. On the plus side, the majority don’t appear to be against the idea.

The meaning of life

The next question got into the philosophical side of things and touched upon something often used to justify death.

The idea that death makes life meaningful has long been used to rationalize death. It is also used as a reason for not trying to reverse biological aging to prevent age-related diseases.

There is nothing at all wrong with growing chronologically older and hopefully wiser, but getting biologically older is the primary risk factor for a myriad of such diseases. Our field is focused on slowing down and even reversing the damage that aging causes to organs and tissues. The goal is to keep people biologically younger and healthy for longer.

It is good to see that these responses largely reject the idea that death is needed to make life meaningful. Unfortunately, the set answers focused on how we live and not how long, which kind of defeats the point of the original question, especially since most of the respondents had expressed positive attitudes towards indefinite lifespans.

Feeling a bit emotional about longevity

The next question delved into the emotional side of the human experience.

While it is not possible to know how longer lives might affect human emotions, we have explored some related concerns. We covered the idea that longevity might lead to eternal boredom and why this is unlikely. The concept that society would stagnate if people lived longer is something that we have also written about. We have also touched upon lost motivation due to increased lifespans.

The truth is that we do not know if or how living indefinitely might change the human experience, assuming it would, but I don’t agree that it’s a reason to let people die from potentially curable age-related diseases.

I prefer to think that given more time, people would use that extra time to focus on long-term plans and ambitions. If you have more years of health and youth, it’s easy to picture having many careers, hobbies, and interests.

We still have a long way to go to get the public on board

The penultimate question itself was reasonable, as it asked about the support of research into indefinitely increasing human lifespans. The issue here is that the set answers included the very loaded “Yes, humans should aim to conquer death”.

The problem is that this isn’t what our field of science is trying to do. Let’s be clear here, rejuvenation biotechnology is not immortality. The goal of the field is not to conquer death. It is to prevent or reverse age-related diseases by targeting the causes of aging.

Rejuvenation won’t stop you from dying in a car crash. It can’t save you from falling off a tall building. While it may improve the immune system, it won’t necessarily prevent death from an infectious disease. There are many ways to die, and only age-related diseases are covered by our field, nothing else.

Even if people have an indefinite lifespan it does not equate to conquering death or immortality. This is why I think this particular question is flawed, because the responses miss the point of rejuvenation biotechnology. As a result, the answers people give here are based on that poor framing.

This is why there is a contradiction in their responses. They are mostly fine with living indefinitely according to their responses earlier in the poll, but they are against it later. It would be great to see these questions asked again with better framing for this particular question. I am willing to bet that the answers would be more in favour of supporting research if the question and answers are framed properly.

Back to the meaning of life again

The poll already touched upon the old idea that death gives life meaning, but for some reason, the poll makers chose to return to the same question in a different way, despite the fact that the majority had already rejected the notion that death made life meaningful.

However, we see a shift and somewhat of a contradiction, again because the framing changed. Phrased this way, more people think life has meaning because it ends, so that presumably means death makes it meaningful.

Ultimately, these results suggest that how a question is asked, along with the possible answers, is really important. I believe the main point is that the poll shows the topic is reaching more public audiences. A decade ago, I would never have dreamed to see something like this, but here we are now with the subject being discussed.

An important caveat

While this is interesting, there are important caveats here. The UK government and other organisations make use of the data collected by YouGovChat, although the extent to which this information is used is unknown.

In other words, while this is interesting, the data should be taken with a pinch of salt. Polls such as this have known limitations. They do not represent the entire population, they are only suggestive of the general sentiment.

If you want to take part and are from the UK, you can join the “Would you choose to live forever if you could?” poll.

Help us to build better advocacy tools and ask the right questions

Public trust is the key that opens all other doors. For a long time, longevity research has needed better tools to understand public opinion. This will help to build trust.

To achieve this, we are supporting the development of a cultural intelligence platform by the Public Longevity Group (PLG). The objective is to develop tools for assessing public opinion by evaluating media coverage and analyzing social media engagement in the area and to formulate effective communication methods to connect with previously overlooked audiences.

Thanks to your support, we are more than halfway to the fundraiser goal, but there’s still time to make an even greater impact!

The LRI Board of Directors is matching all donations up to $25,000 to push us over the finish line. Every dollar you give will be doubled. This will help launch the first data-driven sentiment analysis engine for longevity science.

Donate today, and join us in building the tools for effective longevity advocacy!

Date Posted: November 12, 2025

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Multilingualism Is Associated With Delayed Aging

A recent study of over 80,000 Europeans concluded that speaking more than one language is associated with delayed aging. Further analysis suggested that the protective effect of speaking one foreign language diminished with age, while the protective effect of speaking two or more foreign languages was more robust with aging [1].

Beyond communication

Learning a foreign language and maintaining this knowledge in the long term is not an easy endeavor. However, as research suggests, it can bring benefits that go beyond simply communication and cultural enrichment.

Research on multilingualism (“the regular use of more than one language”) suggests that it has a protective role in delaying cognitive decline and age-associated neurodegenerative diseases. [2-4]. However, those studies have some caveats, such as investigating people with cognitive decline rather than healthy people or having small sample sizes.

In a recent study, researchers sought to address these shortcomings and investigate whether multilingualism influences aging. They utilized data from a large population of 86,149 individuals with a mean age of 66.55 years (age range: 51-90 years) from 27 European countries, excluding people with a diagnosis of dementia.

In this analysis, multilingualism was assessed as an aggregate, country-level percentage of people speaking one, two, three, or more languages. At the same time, individual data was used to estimate the aging rate.

The authors measured this rate by calculating biobehavioral age gaps (BAGs), which represent the difference between an individual’s chronological age and the age predicted by a model. This measure is more sensitive than the indirect markers used in previous studies on this topic. The model that calculates BAG considers both positive and adverse risk factors to which the individual was exposed. Positive BAG values indicate accelerated aging, while negative values suggest delayed aging.

The more the merrier

The researchers performed two types of analysis: cross-sectional analysis, which analyzes data at a single time point, and longitudinal analysis, which allows for the analysis of a population over a period of time. While the results differed slightly, they both point to multilingualism having positive effects.

According to the cross-sectional analysis, people who speak only one language (monolinguals) are 2.11 times more likely to experience accelerated aging. In comparison, people who speak at least one more language are 2.17 times less likely to experience accelerated aging. The exact odds differ depending on the number of languages spoken, with bilinguals 1.3 times less likely to experience accelerated aging, trilinguals 1.96 times less likely, and polyglots who speak four or more languages 1.56 times less likely.

Analyzing this population over time through longitudinal analysis suggests a similar protective effect of language learning, with monolinguals having 1.4 times higher chances of experiencing accelerated aging over time, while the risk is 1.43 times lower for multilinguals, and as previously depends on the number of languages spoken and showing a dose-dependent effect. The results of this analysis showed that bilinguals were 1.11 times less likely to develop accelerated aging, trilinguals 1.25 times, and polyglots speaking four or more languages 1.41 times less likely.

An additional analysis that grouped participants by age suggested the same protective effects. However, it also indicated that the protective effect of speaking one foreign language diminished with age. In contrast, the protective effect of speaking two or more foreign languages remained more robust with aging.

Other factors

The authors of this study noted that many previous studies did not account for confounding factors and exposure to various lifestyle-related and socioeconomic factors, which can all lead to inconsistent results and improper data interpretation. To correct that, they used aggregate country-level data to adjust their analysis for different linguistic, physical, social, and sociopolitical conditions. They observed only minor changes in the magnitude of the protective effect of multilingualism.

They only noted the effects of two factors. The positive impact of delayed aging in polyglots was lost in the cross-sectional analysis following adjustments for immigration status, and in the longitudinal analysis, a positive effect in the bilingual population was lost when the researchers controlled for gender equality.

The authors speculate that since migration is often linked to different stressors, it “can lead to stressful multilingualism,” where acquisition of other languages is done out of necessity and pressure. Such stress and pressure might diminish the positive effect of language learning. However, as the authors discuss, their analysis is lacking a significant amount of data regarding migration, such as whether it was forced or voluntary, the length of stay, migration history, and other relevant details. Therefore, this result should be interpreted with caution.

Their results also suggest that similar negative factors, as in the case of migration, can be present in environments lacking gender equality, thereby contributing to the limited positive effects of multilingualism for people in those environments, suggesting that factors beyond individual lifestyle choices might have a profound impact on aging.

Not the first evidence, but strong evidence

Overall, this study revealed a strong association between multilingualism and a reduced risk of accelerated aging, whereas monolingualism was associated with an increased risk of accelerated aging.

While this study was not the first to show the positive effects of speaking multiple languages, it addressed many shortcomings of previous studies, thereby strengthening the evidence and adding additional support that multilingualism, along with other lifestyle factors, can be incorporated into public health guidelines as a protective factor against accelerated aging.

Although this study draws conclusions from a robust dataset, it cannot establish causality between the observed associations. Further studies, based on experimental or intervention-based designs, are needed to establish causality.

The researchers also point out that their “measures were coarse, and participants likely represented mixed multilingual profiles.” Still, the strength of the observed associations suggests that the observations can be generalized, as they are derived from the broad variability of profiles. However, to identify differences in the level of protection between various multilingual profiles, there is a need for additional studies that incorporate individual-level multilingual metrics such as age of acquisition and proficiency level, as this analysis relied on country-level data, which limited the authors’ conclusions and ability to analyze the impact of those individual factors on aging trajectories.

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Literature

[1] Amoruso, L., Hernandez, H., Santamaria-Garcia, H., Moguilner, S., Legaz, A., Prado, P., Cuadros, J., Gonzalez, L., Gonzalez-Gomez, R., Migeot, J., Coronel-Oliveros, C., Cruzat, J., Carreiras, M., Medel, V., Maito, M. A., Duran-Aniotz, C., Tagliazucchi, E., Baez, S., García, A. M., & Ibanez, A. (2025). Multilingualism protects against accelerated aging in cross-sectional and longitudinal analyses of 27 European countries. Nature aging, 10.1038/s43587-025-01000-2. Advance online publication.

[2] Alladi, S., Bak, T. H., Duggirala, V., Surampudi, B., Shailaja, M., Shukla, A. K., Chaudhuri, J. R., & Kaul, S. (2013). Bilingualism delays age at onset of dementia, independent of education and immigration status. Neurology, 81(22), 1938–1944.

[3] Craik, F. I., Bialystok, E., & Freedman, M. (2010). Delaying the onset of Alzheimer disease: bilingualism as a form of cognitive reserve. Neurology, 75(19), 1726–1729.

[4] Venugopal, A., Paplikar, A., Varghese, F. A., Thanissery, N., Ballal, D., Hoskeri, R. M., Shekar, R., Bhaskarapillai, B., Arshad, F., Purushothaman, V. V., Anniappan, A. B., Rao, G. N., & Alladi, S. (2024). Protective effect of bilingualism on aging, MCI, and dementia: A community-based study. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 20(4), 2620–2631.

Date Posted: November 11, 2025

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New Gene Therapy Robustly Lowers LDL and Triglycerides

A new Phase 1 trial produced encouraging safety and efficacy results for a CRISPR-based gene therapy that silences a gene important for lipid regulation. This therapy might increase adherence and reduce side effects [1].

Addressing the adherence problem

High levels of LDL cholesterol (LDL-C) and triglycerides are a major risk factor for cardiovascular disease and mortality. They can be caused by genetic variations, other diseases like hypothyroidism and diabetes, and environmental factors such as modern eating habits [2]. This dyslipidemia is also age-related, with LDL-C levels tending to rise in older people [3].

Effective therapies, especially against high LDL-C, exist. Statins, a class of cholesterol-lowering drugs that lead to robust reductions in cardiovascular events and related mortality, are a go-to first-line option. However, low adherence and side effects remain a problem, with many patients discontinuing treatment within a year.

In this trial, the company CRISPR Therapeutics tested an experimental gene therapy agent, CTX310, against abnormally high LDL-C and triglyceride levels. The therapy, based on the CRISPR platform, silences the production of ANGPTL3, a protein that is secreted primarily by the liver and plays a key role in regulating blood lipid levels. This protein inhibits the enzymes lipoprotein lipase (LPL) and endothelial lipase, which are crucial for breaking down triglycerides and remodeling high-density lipoprotein (HDL). As a result, higher ANGPTL3 levels lead to higher levels of circulating triglycerides and cholesterol in the blood.

LDL and triglycerides halved

This multicenter, open-label, single-ascending-dose study was conducted in Australia, New Zealand, and the UK and involved 15 adults with uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia. The participants’ median age was 53 years with a range of 31 and 68. 87% were male, 40% had a history of atherosclerotic cardiovascular disease, and 40% had familial hypercholesterolemia, with 33% carrying confirmed genetic mutations. Background lipid-lowering therapies included statins (60%), ezetimibe (53%), and PCSK9 monoclonal antibodies (40%).

The elements of the CRISPR system (SpCas9 mRNA + a single guide RNA targeting ANGPTL3) were encapsulated in lipid nanoparticles (LNPs). The treatment was administered once via IV infusion, and the follow-up period prior to publication of the results was 60 days with a one-year continuation.

The treatment caused a drastic decline in the average ANGPTL3 level at higher doses: up to -79.7% for the 0.7 mg/kg dose. The average level was actually slightly, but not significantly, higher for 0.8 mg/kg: -73.2%. Most importantly, the treatment significantly lowered mean LDL-C and triglyceride levels at 0.8 mg/kg; LDL-C was down by 48.9% and triglycerides by 55.2% at this dose.

Why do we need ANGPTL3, if silencing it seems to benefit us? Like some other genes, it might have lost its evolutionary sense as food became more abundant. By shunting post-meal triglycerides to fat tissue for storage, ANGPTL3 might have helped our ancestors to eat large meals when food was available without burdening the heart and muscle with excess lipid.

Waiting for more robust studies

The trial reported minimal adverse events, indicating a favorable safety profile for CTX310. No dose-limiting toxic effects were observed. However, variability in lipid-lowering effects was noted among participants receiving the same CTX310 dose.

According to the researchers, this variability was not simply dose-related: editing efficacy and lipid responses may be influenced by hepatic steatosis, inflammation, and pre-existing genetic/metabolic profiles, and the cohort itself had mixed phenotypes, as some were primarily high LDL-C, and others had high triglycerides. This likely contributed to differences in lipid-lowering effects even at the same dose. The team calls for more rigorous studies to identify patient-specific predictors and to optimize dosing.

The sample size was also extremely small: only 2-4 patients received each dose, resulting in low statistical power for each cohort. The primary outcome of this Phase 1 trial was safety, and subsequent phases will provide more robust efficacy results.

The cohort was heavily male, and the authors themselves note that few women were enrolled, limiting subgroup assessment. Known sex differences exist in lipid biology, such as menopause-related shifts [4], and they affect responses to biological interventions and in the way people age, so generalizability from this sample is uncertain.

Finally, the effect size was not necessarily larger than that of some existing therapies. However, those require constant administration and can cause considerable side effects.

“Adherence to cholesterol-lowering therapy is one of the biggest challenges in preventing heart disease,” said Steven E. Nissen, M.D., FAHA, a co-author of the study and chief academic officer at the Cleveland Clinic Heart, Vascular and Thoracic Institute. “Many patients stop taking their cholesterol medications within the first year. The possibility of a one-time treatment with lasting effects could be a major clinical advance.”

Yes I will donate❤️

Literature

[1] Laffin, L. J., Nicholls, S. J., Scott, R. S., Clifton, P. M., Baker, J., Sarraju, A., … & Nissen, S. E. (2025). Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3. New England Journal of Medicine.

[2] Yanai, H., & Yoshida, H. (2021). Secondary dyslipidemia: its treatments and association with atherosclerosis. Global health & medicine, 3(1), 15-23.

[3] Liu, H. H., & Li, J. J. (2015). Aging and dyslipidemia: a review of potential mechanisms. Ageing research reviews, 19, 43-52.

[4] Palmisano, B. T., Zhu, L., Eckel, R. H., & Stafford, J. M. (2018). Sex differences in lipid and lipoprotein metabolism. Molecular metabolism, 15, 45-55.

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The Blog

Building a Future Free of Age-Related Disease

Repurposing previous data

Much of the data agrees with existing databases

Verifying the AI’s data

Literature

One by one

The kind of amino acid makes a difference

Using genetic data

Tyrosine reduction as a possible intervention

Literature

Few and far between

The lysosome connection

Rebuilding the blood system

Literature

Mitochondrial transfer is difficult to improve

“Nanoflowers” boost mitochondrial output

“MitoFactories” to the rescue

Putting new mitochondria to work

Literature

Here, I want to quote a press release from Lila. It says, “Lila’s mission is to responsibly achieve scientific superintelligence.” So, they are talking about superintelligence.

Still, “responsibly” implies that this can also be done irresponsibly and probably do some damage. So, how do you do it responsibly, and what could happen if we fail?

About that: it’s always interpretability versus the model’s power. Where are you in this debate? Would you prefer a weaker but more interpretable AI or a stronger but less interpretable one?

I just honestly think that we will soon be faced with this dilemma, where we will have to choose between the power of the model to do things and its actual interpretability, but maybe we’re not there yet.

Let’s move to Lila’s model. Can you give me any more details? For instance, is the reasoning happening on the human language level?

Let’s go back for a second to that “scientific superintelligence.” I’m not asking if AI will replace human scientists. I’m asking how soon it will replace human scientists, and does it bother you in any way?

I agree. I just think that technically, creating such a hybrid system is really hard.

Even if Lila’s vision is fully realized in a few years, we will still have a lot of downstream bottlenecks. What are these bottlenecks that science will face, and what can be done about them?

I have been thinking lately about the difference in public opinion on science and AI. It seems that the public generally loves science but vilifies AI. How do we get out of this?

Can you give me your vision for AI in biology in several years from now, a decade, maybe two? What will it be able to do? How would it change science and human aging?

It’s not that I disagree, I just think that everything about AI is a race. So maybe we will be able, theoretically, to de-black-box everything. We might just not have the time and the resources to do it because everyone’s racing to the goal.

Why older people have significantly worse melanoma cases

Melanoma is attracted to senescent cells

The protein that drives melanoma’s growth

Literature

Every woman’s problem

Delaying ovarian aging

Many mechanisms, one goal

Literature

Targeting the Root Cause of Neuronal Vulnerability

Transitioning from Discovery to Clinic

About Vincere Biosciences Inc.

Making aging-resistant cells

Significant effects on monkeys

Exosomes recapitulate many of the changes

Literature

Primary and secondary sarcopenia

Two studies create a combined picture

Literature

Which way to splice it?

From worms to mice

Restoring the balance

Literature

Finding the right questions

The biggest question is why

The field has come a long way, but there is still much to do

Literature

Public sentiment on living forever or at least indefinitely

The meaning of life

Feeling a bit emotional about longevity

We still have a long way to go to get the public on board

Back to the meaning of life again

An important caveat

Help us to build better advocacy tools and ask the right questions

Beyond communication

The more the merrier

Other factors

Not the first evidence, but strong evidence

Literature

Addressing the adherence problem

LDL and triglycerides halved

Waiting for more robust studies

Literature

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