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Building a Future Free of Age-Related Disease

Nir Barzilai Interview
Date Posted: August 12, 2025
Comments Off on Nir Barzilai: “Positive Evidence for Metformin is Mounting”

Nir Barzilai: “Positive Evidence for Metformin is Mounting”

Dr. Nir Barzilai, the director of the Institute for Aging Research at the Albert Einstein College of Medicine, among his many other titles, is one of geroscience’s most prominent figures. He is everywhere all at once, seemingly collaborating with the entire world, but is best known as a staunch proponent of metformin, the anti-diabetes drug that extends healthspan and lifespan in animal models and maybe in humans, as well as for his fascinating research into centenarians. Recently, a review paper came out that questions metformin’s reputation as a geroprotector. We thought it was the perfect moment to reach out to Dr. Barzilai for an update on his faith in metformin, the long-awaited Targeting Aging with Metformin (TAME) trial, and other exciting topics.

Let’s start with the recent metformin paper that intends to pour some cold water on the idea that metformin is a good gerotherapeutic.

There are 34,731 papers about metformin, which has been around for decades, and most of them are good; the positive evidence is accumulating. The authors of this one decided to talk about the “bad” papers, because the fact that metformin has clinically proven benefits beyond just diabetes is well known.

Metformin didn’t start as an anti-diabetic drug. In the 1950s, this extract of the French lilac was used for osteoarthritis, to prevent flu, and for a variety of remedies when it was noticed that it also lowers glucose. When they gave it to people with diabetes, they said, “Hey, what’s going on? It’s doing other things”. Aging is where it started and where it’s going.

When I do a “metformin and aging” search in PubMed, there are 1,400 papers on that, and the majority are good. In just the last year, there are 111, most of which are good, and they were not quoted in this recent paper. The reason this was brought up is because of an effort by Christensen to look at people who took metformin for diabetes in Denmark. It wasn’t a clinical study; it was just looking at data.

There’s a problem with this approach: the data showed that metformin decreased mortality initially, but not later on. But of course! When it decreases mortality initially, the people who would have died have now passed, and the people who gained lifespan will eventually match the plot. That’s a time-to-event bias. He didn’t talk about this part; he just said at the end, “We didn’t show an effect”.

This Danish study came after another foundational study from the UK, which was also observational and showed that people on metformin not only have half the mortality of people on other drugs, which is true and is good data, but they also had less mortality than people without diabetes.

Let’s explain to our readers that you’re talking about two influential populational studies of metformin. One, from a few years ago, reinforced metformin’s reputation as a gerotherapeutic, and then, a couple of years ago, another study with a somewhat comparable design came out and, according to some opinions, refuted the first one.

“Refute” is not the right word. One study was done in England, the other in Denmark. One of the differences is that the obesity rate in England is 20%, while in Denmark, it’s 5%. Obesity is one of the main reasons people are prescribed metformin in England. So, we are not talking about the same population, and it hasn’t been done the same way. I accept that you can do different studies around the world, but my point is that those were two flawed observational studies, and there are better studies out there.

The most important study that connects metformin with aging is the one that showed that if you give it during COVID, you slash mortality and the rate of long COVID in half. The critics say, “Okay, but this study didn’t reach its primary endpoint”. Their primary endpoint was hypoxia. It’s silly! It’s just a stupid endpoint because metformin isn’t working on hypoxia; it’s working on inflammation, on immunity, on the ability of the body to resist.

So, who cares? You can take any study in the world and find its limitations. That’s our profession. In every journal club, an outsider would think every paper is a bad paper. But no, every paper has some limitations, and we accept a certain idea only when data accumulates. My point is that there’s so much data on metformin. The authors of this new paper include references to all the good studies; they’re just not talking about them.

Then they do another thing that doesn’t make sense: they take the DPP, the Diabetes Prevention Program. The DPP study was concluded around the year 2000. It’s a study where you take non-diabetics who are at risk of diabetes.

Yes, it was basically a prevention study.

Exactly. And they stopped the study after four years, though it was planned for five, because both metformin and lifestyle changes clearly prevented diabetes. If people say metformin was never given to non-diabetics, that’s wrong; it was. In fact, more metformin is probably given to non-diabetics now than to diabetics.

Anyway, the study ended at four years, and the participants were followed up, but what happened? The study found that metformin was good for you, so some people in the control group started taking it. The study also said healthy lifestyle changes were good for you, so some people changed their lifestyle. Conversely, some people who were on metformin stopped taking it, and some people who were on a lifestyle plan stopped doing it. Moving forward, it wasn’t a clinical study anymore; it became an observational study, and they didn’t find much. It’s just another example of a study where all the groups have changed and mixed. To make such a big story about the DPP is ridiculous.

They’re saying this is “emerging” evidence, but it’s not. They’re just taking three studies that are not RCTs [randomized controlled studies]. Then there’s the monkey study published in Cell, which was a big deal. Aging was delayed by eight years on the transcriptomic level. There are so many other good studies on metformin.

Another thing, regarding Rich Miller from the ITP [Interventions Testing Program]. Rich believes that whatever doesn’t work in his animals doesn’t work in humans, but this is the opposite situation! The drug already showed effects in humans. What are you defending? What are you trying to say?

I guess he’s trying to say that we don’t see a lifespan effect in mice, and we also don’t have definitive lifespan data in humans.

But that is wrong. There is a lifespan effect in mice, just not as much as with rapamycin. It’s been recorded by 20-something studies, but Rich ignored something from his own ITP data. They’re missing a very important point: metformin is not for young people; it’s only for old people.

This relates to the antagonistic pleiotropy hypothesis of aging, where not everything that’s good for you when you’re young is good for you when you’re old, and it’s the other way around with drugs. Not every drug for aging is good for the young, and metformin is a perfect example. Whoever takes metformin who doesn’t have diabetes and is not at least 50 years old is making a mistake, in particular if they’re trying to build their muscle or increase their VO2max.

I’m saying this because there’s a new study from the ITP, which re-analyzes their own data and shows that metformin wasn’t good in the first half of the animals’ lives but performed significantly better in the second half of life.

There is also the time-bias issue. For example, there was a paper from China claiming metformin is associated with more Alzheimer’s. Usually, it’s the opposite, but this is what happens: if metformin prevents your mortality in an observational study, you are pushing the endpoint. People might get Alzheimer’s later. There’s a paper coming out in the Journal of Gerontology showing that people on metformin are twice as likely to reach age 90 as other people with diabetes, but if you give metformin and you have decreased mortality, it can look like metformin is bad later on.

You’re saying that if a drug prolongs lifespan, the survivors are actually more likely to eventually get Alzheimer’s simply because they are older, correct?

Right. And that makes a lot of sense.

To summarize, you’re still bullish on metformin. This brings us to the TAME trial, which was designed to answer questions about delaying aging in humans. Can you give me an update on where things stand?

TAME is designed to measure a cluster of outcomes; it doesn’t look at mortality independently. The primary endpoint is a cluster of cardiovascular disease, cognitive decline, cancer, and then mortality. So, you’re not going to get a single mortality number out of it.

Yes, I think TAME’s design is pretty ingenious: a cluster of age-related diseases serving as a proxy for aging. We are all rooting for TAME. What’s happening with it now?

Let me give you a nice update. To call something a “gerotherapeutic” from a preclinical perspective, you have to show that it hits the hallmarks of aging. By the way, metformin hits more hallmarks of aging than any other drug; rapamycin comes close, but metformin is broader.

You also want to show that your animals live healthier and longer. Clinically, you want a placebo-controlled study where you give the drug for months or years and show that although it was given for one purpose, it delayed several other age-related outcomes and decreased overall mortality. I would say that evidence is enough to call something a gerotherapeutic, particularly if it’s already FDA-approved.

It’s important to see what’s happening with SGLT2 inhibitors. These drugs were developed for diabetes, but now we have studies in non-diabetic populations with moderate renal failure. In a study of 4,000 people over three years, their primary endpoints – renal-specific, cardiovascular-specific, and all-cause mortality – were all significantly decreased by 30-40%.

In the same vein, metformin has already been repurposed for many things, just not formally by the FDA. It’s the first line of choice for PCOS, pre-diabetes, COVID, and macular degeneration. Each of these is a different disease, which shows metformin is doing something to several hallmarks, not just metabolism.

That’s a great point about the breadth of the effect. On the other hand, there’s this idea I’ve heard from many people that with all our gerotherapeutics, we are kind of running in circles around the same few pathways that control the trade-off between growth and repair. What do you say to that?

I think it’s almost the opposite. The reason we started arguing about these drugs is because somebody would say, “No, this is not only about metabolism, it does something to the immune system or to mitochondrial function”. The point is the hallmarks of aging are all associated with each other. If you target one hallmark, you’re going to affect the others, and that is the confusion. When you treat aging, you affect many things, which made us argue about the primary mechanism until we understood the hallmarks.

Metformin, from a mechanistic perspective, is doing two main things. On one hand, it has the metabolic pathway effects: activating AMPK, decreasing mTOR, and improving insulin sensitivity by blocking complex I in the mitochondria. The second thing that happens, because it blocks that complex, is there’s less oxidative stress. Because of less oxidative stress, other things happen with inflammation, senescence, and genetic instability. This is why metformin’s effects are quite global.

I want to circle back to TAME because people are very interested in it.

I cannot give you a perfect update because it’s now being handled within ARPA-H. I think there will be two major trials that come out of this. One is going to be from Eli Lilly; they’re going to do a TAME-like study but with their GLP-1 agonist. There are negotiations with the FDA about what they need to show. The investigators might want to add some resilience measurements, but I think the FDA is very determined to see if it affects diseases. This conversation is ongoing, and we’re holding everything because I would love for all four major drug classes to be tested so we can get comparisons.

I’d imagine the TAME design is generalizable, and it would indeed make a lot of sense to test GLP-1 agonists, the rising stars, in the same manner.

Yes. This administration is very good for aging research, and the FDA is engaged. The most important thing about TAME is that it’s a template for the pharmaceutical industry, and that’s probably why Lilly is interested. They see the effect on aging, and they’re saying, “Let’s just do the whole thing and get an indication for aging”.

When you say, “the whole thing,” you mean applying the TAME framework of a cluster of diseases to GLP-1 agonists?

Exactly, and they probably only need 2,000 people to show an effect, but that’s why metformin is so important. Longevity doctors have already adopted it, and it’s the cheapest drug in the formulary. We want to democratize aging, and the best way to do that is to have metformin out there. 90% of the people who should be on it will benefit, and it’s affordable. Healthcare providers will immediately see in the next two years that their healthcare expenses have decreased. Metformin might be more effective than other drugs, but I wouldn’t know unless it’s a head-to-head trial.

Once you do the calculation of the diseases prevented, you’ll be able to afford much more expensive drugs. We calculated that even at its current price, a GLP-1 agonist would be a cost-saving measure for a healthcare provider. They’ll see less Alzheimer’s, fewer strokes, less cardiovascular disease, less kidney failure. It will be so cost-effective that it’s worth the price, and the price will eventually get cheaper.

Let’s switch gears. You’re still doing your centenarian studies. Any interesting findings in the last few years?

I think the most interesting thing is that 60% of our centenarians have functional mutations that decrease the actions of growth hormone. There are many mechanisms, maybe 50 ways to get there, but the IGF-1 pathway is a really good one to target. We actually took a drug that was developed to fight cancer by inhibiting the IGF-1 receptor, gave it to animals, and not only did they live longer, but they also lived much, much healthier. We went from centenarians back to animals with a drug that has already been in humans.

Another thing I’m most excited about goes back to biomarkers. We took proteomic data, measuring 5,000 proteins in a thousand people, and 500 of them were the children of centenarians. They were, on average, eight years younger on a proteomic level than their spouses, but that’s not even the most exciting thing. A lot of those differentiating proteins are related to breakdown of tissues, collagen, and other things. With Tony Wyss-Coray, we’re trying to find which of those 5,000 proteins are specific to certain organs. They could come only from the liver or only from the brain.

We covered that paper last year. It was amazing.

We are continuing with that because we have, for example, people who are “slow agers”. Their proteome says they are younger than their age, but their liver is older than their age. What’s going on? Are they alcoholic? Do they have cancer, or maybe their brain is older? We think in the future, it’s not just about the overall biomarker, but you could find your weakness and go there first. If it’s your kidney, maybe metformin is the best drug for you. If it’s your brain, maybe it’s a GLP-1 agonist.

I just had this thought: what if some centenarians age more uniformly? What if they don’t have those weak spots, and all their organs age more or less simultaneously? That could explain some of their longevity.

That’s a good question. When we look at the children of centenarians versus controls, it looks more like their overall age is lower, rather than them having a specific decrease in unbalanced organs, but they do have a decreased incidence generally. I think it’s a good thought; I would look at it some more. We don’t really do proteomics on centenarians because they are at the end of their lives. That’s why we study their children; we’re interested in their genes. For the centenarians, 30% of them will die in the next year. Maybe the phenotype predicts their demise, or maybe it’s what brought them here, but it’s very hard to deal with.

Of course, you don’t know someone is a future centenarian before they become one, so working with their children is a great approach. Just one last question. How satisfied are you with how things have been going in the longevity field for the past four years since our last interview? Are you excited about where the field is today?

Yes. As the president of the Academy for Health & Lifespan Research, I can say that on one hand, we are so excited about the future and the progress we’re making. We are already telling doctors that there are safe drugs to think about for aging. I gave the keynote at the American Association of Physicians, and people are accepting this premise.

While we’re excited about the research, there’s also a lot of noise growing up in parallel. Sometimes, the noise is even worse than the real progress, and we’re trying to balance that. Without the noise, maybe nobody would have noticed us, but there is noise. One important thing we identified is that although we all have the same mission, we are not using the same terms. If you say “rejuvenation”, it means different things to different people. “Regeneration”, “healthspan”, “longevity”, “anti-aging”, “gerontology”, “geriatrics” – we have lots of terms.

Several organizations hired a rebranding company. They did a lot of work, interviewed people, did studies, and tested things on thousands of people. They came up with a plan based on the fact that if “anti-aging” is our enemy, the best word for us to use is “geroscience”. Why? Because we need the word “science”. To be clear, “geroscience” itself is not the best term for the public, but the plan is to use “geroscience” with something else, depending on the stakeholders, whether we’re talking to lay people, scientists, politicians, or pharma.

We have a roadmap of how we are going to present ourselves and launch a campaign. Although “geroscience” didn’t pick up on its own, with the right marketing, it can become really important and distinguish us from the noise. This is going to be a campaign that hopefully will make us look new, exciting, and innovative.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Yes I will donate❤️
Atrophied Muscles
Date Posted: August 11, 2025
Comments Off on How FGF21 Fights Back Against a Muscle-Wasting Disease

How FGF21 Fights Back Against a Muscle-Wasting Disease

In Aging, researchers have reported on how an increase in FGF21, a myokine that encourages muscle growth, impacts the progression of amyotrophic lateral sclerosis (ALS).

Progressive and fatal

ALS is an age-related disease that is characterized by the degeneration of motor neurons throughout the spinal cord and in the brain, leading to death by respiratory failure three to five years after onset [1]. Last year, the authors of this study conducted a review concluding that the earliest stages of ALS can be detected in skeletal muscle [2], and other work has found evidence that the disease progresses from the muscles to the brain, not the other way around [3].

Identifying the key factors behind this progression, however, remains an uncompleted task. The transcriptome, which represens RNA gene expression, is heavily dysregulated in ALS patients [2]. Which signals represent the disease, and which signals represent a cellular attempt to mitigate the disease, however, remains an open question [4], one that has been investigated for nearly a decade [5].

For example, one of these biomarkers is FGF21, which this research team had previously investigated in this context [6]. Here, they redoubled their efforts in an effort to determine FGF21’s role in ALS and how it may impact the disease.

FGF21 is co-located with atrophied fibers

This study was carried out using muscle biopsies from patients gleaned at this team’s ALS clinic. Like the broader population, they found this disease to be more common in males than females, and the average age of patients was approximately 57.

Compared to biopsies of normal tissue, the FGF21 expression in the muscle of most, but not all, ALS patients was highly elevated as measured by an mRNA analysis. In the spinal cord, some ALS patients had levels below the norm, but others had extraordinarily high levels. While most patients that had high FGF21 in the spinal cord also had high levels in muscle, there were exceptions.

These patterns were mimicked in model mice that express a mutant version (G93A) of a particular antioxidant gene, SOD1, in skeletal muscle. These short-lived mice had much higher levels of FGF21 in both muscle tissue and spinal cord than their unmodified counterparts. While much of this came from the liver, even more originated from the muscle itself.

ALS does not cause every muscle fiber to suffer the same level of atrophy at once; rather, both atrophied and unatrophied fibers can be found within the same biopsy. In human muscle tissue, FGF21 and ALS were found to be co-located; atrophied fibers were found to have much more FGF21 than unatrophied ones.

FGF21 mitigates, not accelerates

An increase in FGF21 in blood plasma was associated with a slower progression and increased survival. Patients with low circulating FGF21 were likely to survive for only 18 months, while patients with high levels survived for an average of 75. Interestingly, a high BMI was associated with greater FGF21.

KLB is the gene that encodes β-Klotho, a co-receptor of FGF21. Its levels varied wildly in ALS patients; before the patients’ deaths, they expressed four times as much KLB as the control group, but a post-mortem examination showed that they expressed only half as much as controls, a finding that was recapitulated in G93A model mice.

Using iPSC technology to generate motor neurons from ALS patients, these findings were recapitulated in nervous tissue as well. Compared to controls, ALS motor neurons had half as much FGF21 but thrice as much KLB, a finding that appeared to be related to the effects of oxidative stress.

ALS-affected cells are much more vulnerable to oxidative stress than unaffected cells. Relatively low levels of hydrogen peroxide, which do not kill most of the control group, killed the majority of ALS motor neurons. Administering FGF21 to these cells increased their viability, although not quite to the level of controls.

FGF21 is myogenic; under normal circumstances, it generates functional tissue and increases strength. These researchers found that it indeed decreases stress in muscle tissue while increasing the number of muscle cells.

In total, the upregulation of FGF21 in ALS appears to be an attempt to mitigate the atrophy and cellular stress that characterize the disease. However, the researchers point to a problem with the FGF21-KLB axis and suggest that this dysfunction is key to the progression of ALS. Further work needs to be done to analyze this axis and determine if and how it can be effectively targeted to stop this deadly disease.

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

Literature

[1] Hardiman, O., Van Den Berg, L. H., & Kiernan, M. C. (2011). Clinical diagnosis and management of amyotrophic lateral sclerosis. Nature reviews neurology, 7(11), 639-649.

[2] King, P. H. (2024). Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review. Neural Regeneration Research, 19(4), 747-753.

[3] Moloney, E. B., de Winter, F., & Verhaagen, J. (2014). ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease. Frontiers in neuroscience, 8, 252.

[4] Verma, S., Khurana, S., Vats, A., Sahu, B., Ganguly, N. K., Chakraborti, P., … & Taneja, V. (2022). Neuromuscular junction dysfunction in amyotrophic lateral sclerosis. Molecular neurobiology, 59(3), 1502-1527.

[5] Benatar, M., Boylan, K., Jeromin, A., Rutkove, S. B., Berry, J., Atassi, N., & Bruijn, L. (2016). ALS biomarkers for therapy development: state of the field and future directions. Muscle & nerve, 53(2), 169-182.

[6] Si, Y., Cui, X., Crossman, D. K., Hao, J., Kazamel, M., Kwon, Y., & King, P. H. (2018). Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis. Neurobiology of disease, 114, 85-94.

Date Posted: August 8, 2025
Comments Off on Mitochondria Transplant Improves Chemotherapy in Lung Cancer

Mitochondria Transplant Improves Chemotherapy in Lung Cancer

Scientists have demonstrated that injecting healthy mitochondria either systematically or directly into the tumor microenvironment boosts the efficiency of a standard anti-cancer therapy [1].

Mitochondria’s dual role in lung cancer

While not the most prevalent type of cancer, lung cancer causes more deaths than any other. Non-small cell lung cancer (NSCLC) accounts for 85% of cases. This is a less aggressive variety but is still deadly in many cases, even when caught early.

Chemotherapy remains the backbone of treatment for advanced NSCLC, but its success is often undermined by two persistent problems: tumor cells’ adaptability and the toxic impact on the immune system. Anti-cancer treatments have also been shown to accelerate aging [2]. A new study from Tongji University School of Medicine and Nantong University in China, published in Cancer Biology & Medicine, suggests a novel way to address both problems by transplanting healthy mitochondria into the tumor environment.

Cells use two major types of energy production. Oxidative phosphorylation (OXPHOS) is facilitated by mitochondria. It is a complex, multi-stage process that takes time and produces many molecules of ATP (the cell’s energy ‘currency’) for every glucose molecule. It requires oxygen and emits CO2 as a byproduct. Glycolysis occurs in the cytoplasm, does not require oxygen, and produces much smaller amounts of ATP for every glucose molecule.

Despite glycolysis being the more ancient and less effective form of energy production, many tumors reprogram cellular metabolism, including mitochondrial function, to suppress OXPHOS and rely more on glycolysis, a shift known as the Warburg effect [3]. This supports rapid growth and contributes to immune evasion by creating a more acidic environment that weakens immune cells.

Those immune cells, especially T cells and natural killer (NK) cells, also depend on mitochondria to perform their tasks. In the harsh tumor microenvironment, cancer cells can even strip mitochondria from incoming immune cells via filament-like tunneling nanotubes, further weakening the immune response. The researchers hypothesized that supplying fresh, functional mitochondria could help on both fronts, restoring metabolic balance in tumor cells to make them more sensitive to chemotherapy and revitalizing immune cells so that they can attack the tumor more effectively.

Mitochondria hurt cancer cells, boost immune cells

The team transplanted mitochondria from energy-rich human heart muscle cells (cardiomyocytes) into NSCLC models, both in vitro and in mice. In vitro, this was done by co-culturing cancer cells with mitochondria, while in vivo, the researchers used two routes: systemic delivery and local delivery via an injection directly into the tumor site.

Mitochondrial transplantation was combined with cisplatin, a DNA-damaging chemotherapy drug that is standard for NSCLC but known for its immunosuppressive side effects. The team compared three major groups: cisplatin alone, mitochondrial transplantation alone, and the combination. In in vivo experiments, subgroups varied by the type (either systemic or systemic plus local) and frequency of mitochondria delivery (either once or twice per week).

In vitro, mitochondrial transplantation by itself did not kill cancer cells. However, when paired with cisplatin, it nearly halved the concentration of cisplatin required to inhibit cell growth by 50% (IC₅₀) from about 12.9 μM to roughly 6.7 μM. Interestingly, systemic delivery exerted a similar, albeit weaker effect. The combination also shifted tumor metabolism back toward OXPHOS, counteracting the Warburg effect. Markers associated with tumor aggressiveness and therapy resistance, including HIF-1α, CD44, and CD133, were all reduced.

In mice injected with NSCLC cells, the combination treatment significantly slowed tumor growth, with the best results achieved in mice that received both local and systemic mitochondria delivery twice a week. Interestingly, systemic delivery was almost as effective.

Mitochondria tumors

With either method of delivery, tumor stemness/aggressiveness markers such as HIF-1α, CD44, and CD133 were decreased, while markers of programmed cellular death (apoptosis) in cancer cells were increased. Additionally, there was a considerable increase in reactive oxygen species (ROS) in cancer cells. These results suggest that even though the systemic immune boost due to the immune mitochondria uptake is probably a big part of the effect, the tumor cells also end up ingesting those mitochondria, which pushes them metabolically and structurally toward greater vulnerability.

Relevance for future anti-aging treatments

“This research introduces a powerful dual-action strategy,” said Dr. Liuliu Yuan, lead investigator of the study. “By replenishing immune cells with functional mitochondria, we are not just enhancing their energy but restoring their ability to fight. At the same time, tumor cells become more vulnerable to chemotherapy. It’s like rearming the immune system while disarming the tumor. This could be a promising avenue for patients who don’t respond well to conventional treatment.”

As promising as the results are, they come from early-stage research. The delivery method for mitochondrial transplantation, its durability, and its effects in the complex physiology of human cancers will all require further testing. Scaling up mitochondrial production and ensuring consistent quality will also be practical hurdles. However, if mitochondrial transplantation is mastered, it can have implications far beyond anti-cancer treatments, particularly for future anti-aging therapies.

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

Literature

[1] Lin, S., Yuan, L., Chen, X., Chen, S., Wei, M., Hao, B., … & Fan, L. (2025). Mitochondrial transplantation sensitizes chemotherapy to inhibit tumor development by enhancing anti-tumor immunity. Cancer Biology & Medicine.

[2] Shafqat, S., Chicas, E. A., Shafqat, A., & Hashmi, S. K. (2022). The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence. The Journal of Clinical Investigation, 132(13).

[3] Potter, M., Newport, E., & Morten, K. J. (2016). The Warburg effect: 80 years on. Biochemical Society Transactions, 44(5), 1499-1505.

Lifespan Alliance
Date Posted: August 7, 2025
Comments Off on Lifespan Alliance Launch & New Leadership at LRI

Lifespan Alliance Launch & New Leadership at LRI

Mountain View, California — Lifespan Research Institute, a nonprofit leader in longevity science and advocacy, announces the launch of the Lifespan Alliance, a sponsorship initiative uniting mission-driven companies and visionary organizations dedicated to extending healthy human lifespan.

Member organizations, including launch sponsors AgingBiotech.info, Immortal Dragons, Rejuve.bio, Ora Biomedical, and Quadrascope, have the opportunity to collaborate in a variety of initiatives that integrate science and advocacy, building a high-trust ecosystem focused on delivering real-world impact to address the diseases of aging.

More information on the Lifespan Alliance is available at Lifespan Research Institute’s website.

Lifespan Research Institute Board Members Keith Comito and Dr. Oliver Medvedik have stepped into the roles of Chief Executive Officer and Chief Scientific Officer, respectively, to lead this initiative and strengthen Lifespan Research Institute’s scientific and outreach programs. These appointments reflect LRI’s commitment to combining visionary leadership with scientific rigor, and to leverage decades of experience in ecosystem-building to create a network capable of strategically identifying and overcoming core bottlenecks in aging research.

KeithOliver

“Aging research is at a critical inflection point,” said Keith Comito. “What we do now will shape our future and that of generations to come. At Lifespan Research Institute, we’re focused on uniting the public and the field around the most promising initiatives to rapidly turn science into real-world therapies that extend healthy human life.”

As part of its commitment to advancing initiatives with the greatest potential to extend healthy life through science, innovation, and collaboration, the Institute has also revitalized its Scientific Advisory Board. Newly appointed members include distinguished researchers and science communicators such as Drs. Felipe Sierra, Irina Conboy, and Matt Kaeberlein.

“I’m excited to be part of this reinvigorated and refocused organization,” said Dr. Oliver Medvedik. “Our unified mission of research and outreach aims to equip stakeholders with accurate, actionable information in longevity biosciences, and to advance scientific understanding of the fundamental processes of aging. I believe our work is essential to guiding medicine toward a new frontier of scientifically validated anti-aging interventions.”

Backed by new leadership, a distinguished Scientific Advisory Board, and the Lifespan Alliance, Lifespan Research Institute is committed to turning bold ideas into real-world impact, advancing therapeutics that treat aging as a modifiable biological process, while also building the public trust necessary to hasten the arrival of therapies which can extend healthy human life.

To learn more, visit the redesigned website.

Media Contact:

Christie Sacco Marketing Director

Stem cells
Date Posted: August 7, 2025
Comments Off on A Better Extracellular Matrix Makes Aged Cells Act Youthful

A Better Extracellular Matrix Makes Aged Cells Act Youthful

Researchers have found that growing older cells in a youthful medium causes them to behave and function more like younger cells, suggesting a new method of creating stem cell-based therapies.

Cultivating patient-derived cells

For some time, mesenchymal stem cells (MSCs), which can be used to differentiate into multiple functional cell types, were thought to be immune privileged in that foreign (allogeneic) MSCs would not be attacked by the host’s immune system. Later experiments, however, found this to be false [1] and that their contributions were more likely to be due to their beneficial signaling effects [2], as the cells themselves were short-lived against a hostile immune system.

Ideally, cells would come from patients themselves, obviating the risks and concerns of allogeneic cells. However, cells taken from older patients are themselves affected by aging, and restoring these cells’ youthful abilities is its own challenge.

The researchers had previously done similar cellular experiments in a decellularized extracellular matrix (ECM), which boosted these older cells’ proliferation abilities [3]. This time, however, they cultivated one group of adipose-derived MSCs (AD-MSCs), derived from volunteers over the age of 65, in ECM Plus, a medium that is created by stem cells found in human amniotic fluid [4]. This cultivation medium contains various collagens, glycoproteins, and basement proteins that are part of the stem cell niche.

As youthful controls, the researchers used Wharton’s Jelly (WJ) cells, which are derived from part of the umbilical cord. They noted that younger AD-MSCs may have been preferable, but these cells’ performance varies greatly due to such factors as fat mass, sex, from where in the body they are derived, and even how they are prepared [5]. They also used tissue culture plastic (TCP) as a medium for an aged control group, as they found it impossible to create an artificial ECM based on aged tissue that could serve as a counterpart of ECM Plus.

Multiple improvements in cellular function

The difference in cultivation medium yielded strong results. Compared to the TCP group, aged AD-MSCs cultured on ECM Plus had fewer markers of cellular senescence, an increased marker of early-stage stemness, longer telomeres, reduced signs of oxidative stress, and less death by apoptosis within the first five passages.

Proliferation was also increased. The ECM Plus group generated more colony-forming units, and the colonies that were formed were more able to differentiate into other cellular types. This improvement was independent of cell type; given the proper stimuli, MSCs cultivated in ECM Plus differentiated into more cartilage-forming cells (chondrocytes), neural progenitor cells, fat cells (adipocytes), and bone-forming cells (osteoblasts). The researchers found that cultivation in this medium caused osteoblasts generated from AD-MSCs or WJ cells to generate substantially more bone, and these cells were much less likely to become adipocytes instead.

The researchers also tested how well these cells respond to an inflammatory environment. Cells generated on ECM Plus created far more anti-inflammatory factors when exposed to the well-known inflammation inducer TNF-α.

“Taken together, these results demonstrate that maintenance of AD-MSCs on ECM Plus remarkably restores the ability of the cells to self-renew, undergo differentiation into multiple cell lineages, including osteogenesis, in vivo, and produce trophic factors.”

Better mitochondria and gene expression

In another experiment using different sets of cells, the researchers took a closer look at oxidative stress and overall mitochondrial function. They found that, in this area, the AD-MSCs cultivated on ECM Plus were more like WJs than the AD-MSCs cultivated on TCP were. The ECM Plus group had less proton leakage and more youthful respiration overall, including an increase in efficiency. A supercomplex responsible for electron transport was more effective in the ECM Plus group.

The benefits were also found in gene expression. Unsurprisingly, cells cultivated in ECM Plus had significantly different gene expression relating to ECM interactions than the TCP group, and the reduced senescence was seen in this area as well. Cellular proliferation, a reduction in the senescence-associated secretory phenotype (SASP), reduced apoptosis, and differentiation potential, including differentiation into multiple lineages, were also found to be positively impacted in the realm of gene expression. Additionally, cells cultured on ECM Plus were more likely to express HLA-DR, a compound that encourages the proliferation of T cells.

While these are still aged cells, these findings suggest that a proper growth medium may be the key to effectively using patient-derived (autologous) treatments rather than potentially hazardous and short-lived allogeneic cells. If one’s own stem cells can be refined, cultivated, and properly differentiated, they can serve as treatment vectors for multiple age-related diseases. However, this was entirely a cellular study and there were no animals involved; future in vivo work will have to be conducted to determine the true abilities of cells cultivated in this way.

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

[1] Ankrum, J. A., Ong, J. F., & Karp, J. M. (2014). Mesenchymal stem cells: immune evasive, not immune privileged. Nature biotechnology, 32(3), 252-260.

[2] Munoz, J. R., Stoutenger, B. R., Robinson, A. P., Spees, J. L., & Prockop, D. J. (2005). Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proceedings of the National Academy of Sciences, 102(50), 18171-18176.

[3] Block, T. J., Marinkovic, M., Tran, O. N., Gonzalez, A. O., Marshall, A., Dean, D. D., & Chen, X. D. (2017). Restoring the quantity and quality of elderly human mesenchymal stem cells for autologous cell-based therapies. Stem Cell Research & Therapy, 8(1), 239.

[4] Block, T., Creech, J., da Rocha, A. M., Marinkovic, M., Ponce-Balbuena, D., Jiménez-Vázquez, E. N., … & Herron, T. J. (2020). Human perinatal stem cell derived extracellular matrix enables rapid maturation of hiPSC-CM structural and functional phenotypes. Scientific reports, 10(1), 19071.

[5] Tsekouras, A., Mantas, D., Tsilimigras, D. I., Moris, D., Kontos, M., & Zografos, G. C. (2017). Comparison of the viability and yield of adipose-derived stem cells (ASCs) from different donor areas. In vivo, 31(6), 1229-1234.

Nicotine
Date Posted: August 6, 2025
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Nicotine Consumption Improves Motor Functions in Male Mice

A recent study reported that long-term nicotine consumption had a positive impact on motor function in male mice. The beneficial effects were mediated by sphingolipid and NAD+ metabolism [1].

Two faces of tobacco smoking

Smoking tobacco is widely considered detrimental to health for multiple good reasons, as it has been associated with increased risks of cancer [2], type 2 diabetes [3], and premature mortality. [4]. However, there is also a lesser-known, different face of smoking. Epidemiological studies have reported associations between smoking and positive effects on the risk of certain inflammatory and neurodegenerative diseases [5], such as Parkinson’s disease [6] and type I diabetes [7].

Those positive associations are most likely due to the effects of nicotine and not the other components of tobacco smoke, especially since recent research has linked nicotine to increased NAD+ biosynthesis and improvements in metabolic resilience [8]. These benefits were observed at nicotine concentrations much lower than those experienced while smoking, suggesting the need for investigating dose-dependent nicotine effects.

Youthful motor functions

In this study, the researchers investigated the long-term effects of nicotine by adding nicotine to mice’s drinking water at low or high doses starting when mice were 8 weeks of age and continuing for 22 months.

In aged mice that received nicotine, the researchers observed increased locomotor and general activity, enhanced motor strength and endurance, and reduced anxiety-like behaviors compared to aged controls, especially in mice that received higher nicotine doses. The researchers reported that the behavioral patterns of aged mice that received the highest dose of nicotine were most similar to those of the young mice. Also, postural dynamics, which assess how the body maintains balance and stability, of nicotine-treated aged mice showed patterns more similar to those of young controls.

These observations suggest a protective effect of nicotine on motor functions and anxiety-like behavior. Such a protective effect was not observed for cognitive function since the researchers didn’t observe significant differences between groups in memory performance tests.

Linking metabolism with motor functions

A metabolic analysis followed the behavioral and motor function observations. The researchers observed no significant differences between nicotine-treated and untreated aged mice in glucose tolerance tests, insulin tolerance tests, or body weight. However, there were alterations in the distribution of adipose tissue, with the group that received the highest nicotine dose having an elevated visceral-to-subcutaneous fat ratio.

The researchers analyzed all the metabolites across multiple organs, which revealed changes in metabolism caused by nicotine consumption and suggested that both the low dose and the high dose of nicotine partially reversed age-associated metabolic changes. This analysis revealed that nicotine alters the levels of many energy-related metabolites, including changes in amino acid and NAD+ metabolism, suggesting to the researchers that nicotine modulates energy-related metabolic pathways.

These changes in metabolic pathways were also linked to motor functions in aged mice. An analysis of the high-dose group revealed a correlation between significantly altered metabolites and locomotor behaviors.

The researchers concluded that their “findings suggest that nicotine exerts its effects on motor function in aged mice by reshaping metabolic networks, primarily through glucose and lipid-related pathways,” with white adipose tissue being the central mediator of these nicotine-induced metabolic changes. They believe that increased energy expenditure might be responsible for the improved motor performance of nicotine-treated mice.

Behavior-Metabolome Age Score

To quantify the effects of nicotine on biological aging, the researchers developed a composite score called the Behavior-Metabolome Age Score (BMAge score). It includes results from multiple behavioral assays and metabolic profiles from multiple tissues.

The BMAge score of the aged mice treated with high nicotine doses showed the most similarities to that of the young animals. In contrast, the group that received a lower nicotine dose showed intermediate results. While BMAge is useful in these experiments, since it’s a new tool, it should be validated on different cohorts.

Shifting microbiotal composition

Due to the nicotine delivery method (drinking water), nicotine had direct contact with the intestine, and it could impact gut microbiota. Therefore, the researchers tested whether the nicotine impacted microbes in the gut by sequencing the mice’s fecal samples every 4 weeks, starting at 12 months of age. The results revealed a nicotine-induced shift in microbial communities’ structures and found that nicotine treatment was associated with the upregulation of gut microbes known for supporting gut homeostasis and anti-aging effects.

Profiling of microbiota-derived metabolites also revealed substantial nicotine-associated shifts in metabolic profiles. In particular, there were changes to metabolites of the sphingolipid pathway and a decrease in ceramide, which has been linked to age-associated metabolic disorders [9]. In the plasma of high-dose nicotine-treated mice, they also observed increased sphingomyelin and an elevated sphingomyelin/ceramide ratio, which they suggest could serve as an age-related biomarker.

Nicotine administration also substantially altered the expression of enzymes involved in sphingolipid metabolism as well as increased the levels of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, which is in line with increased NAD+ levels in muscles. The essential role of these enzymes in nicotine-mediated sphingolipid and NAD+ metabolism remodeling was confirmed using mouse myoblast cell cultures.

Context-dependent findings

All in all, the researchers concluded that nicotine-induced NAD+ availability positively impacts energy metabolism in aged mice and impacts sphingolipid turnover. These metabolic changes were correlated with improved motor performance and molecular profiles similar to those of young mice.

Under the conditions tested, the researchers didn’t observe any organ toxicity or adverse effects resulting from long-term nicotine intake; however, they caution against extrapolating the findings to humans, since there are known risks regarding nicotine, such as its addictive nature. The researchers also investigated nicotine only in male mice and didn’t address any potential sex-dependent differences.

While this study shows a positive impact of nicotine, the researchers discuss that previous literature showed different, sometimes conflicting results regarding the effects of nicotine. They believe that the differences stem from the route of delivery, length of treatment, and the dose, making the biological effects of nicotine treatment context-dependent.

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

[1] Jia, S., Jing, X., Wang, R., Su, M., Wang, P., Feng, Y., Ren, X., Tu, L., Wei, P., Lu, Z., Jia, Y., Hong, F., Mo, Z., Zou, J., Huang, K., Yan, C., Zou, Q., Wang, L., Zhong, G., Zeng, Z., … Liu, X. A. (2025). Nicotine Reprograms Aging-Related Metabolism and Protects Against Motor Decline in Mice. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e15311. Advance online publication.

[2] Grando S. A. (2014). Connections of nicotine to cancer. Nature reviews. Cancer, 14(6), 419–429.

[3] Chen, Z., Liu, X. A., & Kenny, P. J. (2023). Central and peripheral actions of nicotine that influence blood glucose homeostasis and the development of diabetes. Pharmacological research, 194, 106860.

[4] GBD 2021 Tobacco Forecasting Collaborators (2024). Forecasting the effects of smoking prevalence scenarios on years of life lost and life expectancy from 2022 to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet. Public health, 9(10), e729–e744.

[5] Piao, W. H., Campagnolo, D., Dayao, C., Lukas, R. J., Wu, J., & Shi, F. D. (2009). Nicotine and inflammatory neurological disorders. Acta pharmacologica Sinica, 30(6), 715–722.

[6] Ascherio, A., & Schwarzschild, M. A. (2016). The epidemiology of Parkinson’s disease: risk factors and prevention. The Lancet. Neurology, 15(12), 1257–1272.

[7] Wei, Y., Edstorp, J., Feychting, M., Andersson, T., & Carlsson, S. (2023). Prenatal and adult exposure to smoking and incidence of type 1 diabetes in children and adults-a nationwide cohort study with a family-based design. The Lancet regional health. Europe, 36, 100775.

[8] Yang, L., Shen, J., Liu, C., Kuang, Z., Tang, Y., Qian, Z., Guan, M., Yang, Y., Zhan, Y., Li, N., & Li, X. (2023). Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity. Nature communications, 14(1), 900.

[9] Laurila, P. P., Wohlwend, M., Imamura de Lima, T., Luan, P., Herzig, S., Zanou, N., Crisol, B., Bou-Sleiman, M., Porcu, E., Gallart-Ayala, H., Handzlik, M. K., Wang, Q., Jain, S., D’Amico, D., Salonen, M., Metallo, C. M., Kutalik, Z., Eichmann, T. O., Place, N., Ivanisevic, J., … Auwerx, J. (2022). Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia. Nature aging, 2(12), 1159–1175.

Human Augmentation Summit
Date Posted: August 5, 2025
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Augmentation Lab Announces the Human Augmentation Summit

Join us on August 23, 2025, at the MIT Media Lab in Cambridge, MA, for a full-day summit exploring the frontiers of human potential and longevity. The 2025 Human Augmentation Summit is a gathering of creators – from innovative startups and global companies to independent researchers and artists – all shaping the future of the human condition.

Expect a day packed with live demos, provocative talks, a live in-person Q&A from Stephen Wolfram, immersive exhibits, and hands-on tech experiences that push the boundaries of what it means to be human.

Speakers & Special Guests: Stephen Wolfram, Curt Jaimungal from Theories of Everything, Nataliya Kosmyna, Pat Pataranutaporn, Albert Nerenberg, and more TBA!

Register to Attend

Want to Exhibit your Project, Startup, or Company? Apply by August 15.

EVENT DETAILS

What: 2025 Human Augmentation Summit & Exhibition

When: 9 AM – 9 PM (+ Afterparty) | Saturday, August 23, 2025

Where: MIT Media Lab, Cambridge, MA

Who: Researchers, developers, artists, founders, futurists, and anyone curious about the augmented human future

Areas of exhibited work include:

  • Intelligence: AI & Cognitive Augmentation
  • Embodiment: Cyborgism, Sensors & Bio-Interfaces
  • Biology: Longevity, Genetics, Biotech, Biohacking
  • Networks: Digital Civilization & Collective Intelligence
  • Worldviews: Spiritual, Ethical & Civilizational Frames
  • Design & Ventures: Making it Real
  • Complexity: Planetary Intelligence & Simulated Futures
  • Governance: Power, Norms, and Control of Tech
  • Consciousness: Subjectivity, Psychedelics, and Mind Design

About Augmentation Lab:

They are a trans-disciplinary community of philosopher-builders developing technologies to enhance the human condition, led by their co-founders Dünya Baradari from MIT Media Lab and Aida Baradari from Harvard.

They’re joined by this summer’s lead Summit and Residency team: Mian Irtiza Aftab from SCAD, Yuvraj Virk from UIUC, Jared from Berkeley and WashU, Alice Cai from MIT Sloan, Parth Raghav from VibeCheck, and Addy Cha from Ekkolapto Research.

Contact, Website, and Social Media:

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Intestinal wall
Date Posted: August 5, 2025
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Study Paves Road for Oral Delivery of Proteins

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

Getting rid of the needle

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

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

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

Using antibodies did the trick

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

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

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

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

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

Not exactly the oral route, for now

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

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

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

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

Literature

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

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

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

Brain and DNA
Date Posted: August 4, 2025
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A Brain Clock for Finding Rejuvenating Medications

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

Deciding which -omic to use

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

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

Large datasets for an accurate clock

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

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

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

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

Beneficial perturbations

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

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

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

Effects in mice

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

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

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

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

Literature

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

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

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

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

Human brain
Date Posted: August 1, 2025
Comments Off on Study Finds Metformin’s Action Is Regulated by the Brain

Study Finds Metformin’s Action Is Regulated by the Brain

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

The brain connection

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

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

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

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

The metformin-specific protein

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

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

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

Aim for the brain!

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

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

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

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

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

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

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

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

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

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

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

Rejuvenation Roundup July 2025
Date Posted: August 1, 2025
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Rejuvenation Roundup July 2025

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

Team and activities

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

Interviews

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

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

Advocacy and Analysis

The Tale of One Tower: SF-Based Vertical Longevity Village: In downtown San Francisco, an entire tower is becoming a hub for longevity, AI, crypto, and robotics. It just hosted its first longevity conference.

Research Roundup

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

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

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

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

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

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

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

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

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

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

Blood vessel in boneNon-Toxic Stem Cell Transplantation Prevents Cancer in Mice: Scientists have developed a protocol for hematopoietic stem cell transplantation that reconstructs a healthy blood system and prevents blood cancers in old mice while also reducing toxicity.

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

Lungs

Engineered Stem Cells Reduce Lung Fibrosis in Mice: In Molecular Therapy, researchers have described their creation of cells that express the regenerative factor GDF11 and found that they ameliorate fibrosis in a mouse model.

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

Deer antlersVesicles From Antler Cells Restore Bone in Monkeys: Researchers publishing in Nature Aging have discovered that extracellular vesicles (EVs) derived from antler blastema progenitor cells (ABPCs) restore bone mass to rhesus macaques.

FDA-Approved Drug Combo Rescues Alzheimer’s in Mice: Scientists have creatively used large databases of existing FDA-approved drugs and electronic medical records to locate candidates that are potentially effective against Alzheimer’s.

Human organsOrgan-Specific Aging Analysis Reveals Disease Connections: A recent study explored the differences in the speed of organ aging. The researchers have built models that can predict the odds of diseases and mortality risk based on organ-specific proteins found in plasma.

A Gene That Keeps Cells Under Control: Researchers publishing in Cell Stem Cell have investigated the function of the gene DNMT3A and found that it has wide-ranging effects beyond methylation.

Older people walking7,000 Steps a Day Are Enough for Most Benefits: A massive new meta-analysis confirms that 10,000 daily steps are not required for most of the health benefits of walking. Around 7,000 seems to be the sweet spot.

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

Black 6 miceRejuvenating Muscles in Mice With Senomorphic Treatment: A recent study investigated senescence in mouse and human skeletal muscle tissue, demonstrating that the antiviral drug maraviroc reduces senescence and improves muscle health in aged mice.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

News Nuggets

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

Immortal Dragons Launches $40M Longevity Fund: Immortal Dragons, a purpose-driven longevity fund headquartered in Singapore, today announced its unique approach to investing in radical life extension technologies.

Coming Up

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

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

Brain in skull
Date Posted: July 31, 2025
Comments Off on Senescent Cells, Osteoporosis, and Alzheimer’s Are Linked

Senescent Cells, Osteoporosis, and Alzheimer’s Are Linked

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

Beyond the brain

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

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

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

Nerve amyloids affecting bone tissue

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

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

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

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

A SASP factor can cause amyloid aggregation

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

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

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

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

Literature

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

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

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

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

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

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

Black 6 mice
Date Posted: July 30, 2025
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Rejuvenating Muscles in Mice With Senomorphic Treatment

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

Aging muscle tissue

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

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

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

Senescence in muscles

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

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

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

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

Rejuvenating muscles

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

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

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

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

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

Regulating senescence and the SASP

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

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

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

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

Potential therapeutic candidates

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

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

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

Literature

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

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

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

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

Viva Frontier Tower
Date Posted: July 29, 2025
Comments Off on The Tale of One Tower: SF-Based Vertical Longevity Village

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

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

How does a group conquer a big city?

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

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

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

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

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

It takes a vertical village

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

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

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

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

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

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

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

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

The summit on the 11th floor

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

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

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

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

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

Viva Frontier Tower 1

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

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

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

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

Viva Frontier Tower 2

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

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

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

One tower fits all

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

Viva Frontier Tower 3

The tower’s plan. Fancy visiting the Spaceship?

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

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

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

Viva Frontier Tower 4

The longevity floor sports a quirky semi-industrial design.

Ich bin ein Berliner

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

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

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

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

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

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

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

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Knee arthritis
Date Posted: July 28, 2025
Comments Off on Fighting Osteoarthritis by Targeting Fatty Acids

Fighting Osteoarthritis by Targeting Fatty Acids

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

Fats in the wrong place

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

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

SESN2 is broadly beneficial against arthritis in mice

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

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

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

Establishing the link

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

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

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

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

Literature

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

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

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

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

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

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

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

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