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Building a Future Free of Age-Related Disease

Public Longevity Group

Lifespan Research Institute Launches Public Longevity Group

[Mountain View, September 17, 2025] — Lifespan Research Institute (LRI) today announced the launch of the Public Longevity Group (PLG), a new initiative focused on bridging the cultural gap between scientific breakthroughs in aging and their public acceptance. To kickstart its work, PLG has opened a crowdfunding campaign to develop tools that measure and strengthen public trust in longevity science.

While the science of longevity biotechnology continues to advance, skepticism and cultural resistance limit progress, with some studies showing that more than half of Americans would reject a safe, proven therapy to extend life. This hesitation poses risks of raising costs, delaying health-promoting regulation, and slowing the delivery of treatments that could combat age-related diseases and extend healthy lifespan.

“The breakthrough that unlocks all other breakthroughs is public trust,” said Sho Joseph Ozaki Tan, Founder of PLG. “Without it, even the most promising therapies may never reach the people they’re meant to help. PLG exists to change that.”

“Persuasion is a science too,” said Keith Comito, CEO of Lifespan Research Institute. “To bring health-extending technologies to the public as quickly as possible, we must approach advocacy with the same rigor as our research. With PLG, we’ll be able to systematically measure and increase social receptivity, making the public’s appetite for credible longevity therapies unmistakable to policymakers, investors, and the public itself.”

PLG is developing the first data-driven cultural intelligence system for longevity—a platform designed to track real-time sentiment, test narratives, and identify which messages resonate and which backfire. Early tools include:

  • The Longevity Cultural Clock: a cultural barometer mapping readiness and resistance across demographics and regions.
  • Sentiment Dashboards: real-time monitoring of public, investor, and policymaker perceptions.
  • Narrative Testing Tools: data-driven analysis that will enable robust pathways to public support.

The crowdfunding campaign will provide the initial $100,000 needed to launch these tools, creating the cultural foundation required for healthier, longer lives.

With a lean, data-driven team, the group aims to provide open-access cultural insights for advocates and policymakers while offering advanced analytics to mission-aligned partners.

Campaign Timeline:

  • Campaign completion: November 2, 2025
  • Dashboard development: Dec 2025 – Feb 2026
  • First survey deployment: Feb – Apr 2026
  • Beta dashboard launch: May 2026
  • First public insight report: June 2026

Supporters can contribute directly at: https://lifespan.io/campaigns/public-longevity-group/

The PLG campaign is sponsored by the members of LRI’s Lifespan Alliance, a consortium of mission-aligned organizations that believe in the promise of extending healthy human lifespan. Newly-joined members include OpenCures, AgelessRx, and Lento Bio.

About Lifespan Research Institute

Lifespan Research Institute accelerates the science and systems needed for longer, healthier lives by uniting researchers, investors, and the public to drive lasting impact. LRI advances breakthrough science, builds high-impact ecosystems, and connects the global longevity community.

Media Contact:

Christie Sacco

Marketing Director

Lifespan Research Institute

christie.sacco@lifespan.io

(650) 336-1780

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 ethical journalism and sustains our future.
Laura Minquini Interview

Laura Minquini on the Quest for Female Longevity

Laura Minquini is not a scientist, but that hasn’t stopped her from joining the front lines of the war on aging: specifically, female reproductive aging. Several years ago, after a successful stint in consumer technology, Laura discovered the longevity field when decentralized science was all the rage. Inspired by VitaDAO’s success, she founded AthenaDAO, a decentralized autonomous organization devoted to female health and longevity. Now comes the next step: AthenaBio, a more conventional 501(c)(3) nonprofit with the same broad focus. We talked with Laura about her journey and why female longevity requires special attention (and more female billionaires).

Tell me about your journey into longevity and your personal connection to the field.

First, I’m not a scientist. I got into longevity after we sold my other company. I was looking for a mission, and by pure fluke, while volunteering with my dog, who was still a puppy, at retirement homes, I discovered how we age. I wanted to do something about that.

Let’s take a step back. What was the company?

I started as a fashion editor. When I moved from Canada to Paris, I went into the business side, doing trend forecasting and qualitative research for companies like LVMH. This was before everything was available on Instagram and Google. You had to be part of the industry to have access.

Then I had an opportunity to start a consumer tech company. My business partner and I were the first to do licensed accessories for Apple in Europe. We did design, manufacturing, distribution, everything in between. I call it my MBA in business. We were in Apple stores, Amazon, and fashion distribution, selling across the globe.

It was super interesting and super fun, but it wasn’t what I thought my life would be. My partner wanted to focus on his other business, and I didn’t want to keep doing this. We said, “Let’s call it a day.” Because of how the market was, it was okay to do that, but then you have this moment of, “What do I want to do next?” I looked for a while before I found it.

After we sold it, I wanted to do something interesting that had impact and would make some money. Volunteering with my dog at retirement homes made me think, “Oh my God, this needs help.”

I did a market study and went to Aging 2.0 in San Francisco, thinking, “Tech and aging, that’s how we’ll figure it out.” I hated it. We were talking about diapers and data systems. I thought, “This is not how we’re going to change how we age.”

Then I met my first longevity biotech founder and started reading about the biology of longevity. I thought, “Okay, this is it. Rejuvenation and stopping aging.” Not everybody wants to live forever, but everybody would love to age better and be healthy, whether their goal is 80, 100, or 150.

People should have a choice.

Yes. If you want to call it a day at 80, call it a day at 80. If you want to live forever, live forever. The big question is having health or not having health. For that, we need to figure out the biology.

I got very passionate about it around the pandemic. You probably remember this app called Clubhouse, where you could talk to people you would never otherwise reach. Nathan Cheng and I started panels called The Future of Longevity. We had George Church, David Sinclair, Matt Kaeberlein – everybody who is someone in longevity. We never would’ve had access to these people if not for that app. People were bored at home, so they joined. It was a crazy time, but that was the interesting thing about it: you could have conversations that wouldn’t otherwise happen.

A friend introduced me to Jennifer Garrison, who was working on ovarian aging. Meeting her changed everything. I realized what a huge change menopause is for women, and that became my focus.

I don’t think women are going to have longevity unless we figure out that part of the equation. Women live longer, but they live longer postmenopausal, which is in many ways a compromised state of health.

Four years ago, we started AthenaDAO to fund translational research for women’s health. As a non-scientist, my mission is to bring more capital and attention to scientific research.

I don’t have the temperament to be an influencer. I don’t want to sell supplements. I get that humans want to know what to buy and do today, and that’s why all this placebo works so well, but to live to a thousand years, or whatever people want – or, more basically, for women not to spend a third of their lives in a compromised state – we need to understand biology and stop some of its processes.

That means science and research. Not supplements, meditation, red light, or protocols. Literally therapies.

I agree. Those are Band-Aids.

Think of it: for how many years did Americans battle with weight gain?

Until the GLP-1 drugs came.

Yes. One drug, and everything changed. You can take all the supplements and do all the protocols you want. The only thing that will ever make a difference is when we start having therapies for these things.

I know you as the leader of AthenaDAO, which started during the DAO craze. I understand it’s now morphing into AthenaBio, a more traditional nonprofit.

AthenaDAO is still alive. We’re advancing the assets we funded and functioning as an advocacy resource and network for women and researchers interested in female health.

AthenaBio is about getting more capital allocated. When I started AthenaDAO, they asked, “Why don’t you make this a foundation?” I went against it, and I think we did the right thing then. Now is the right time for a foundation, a 501(c)(3) nonprofit.

These are separate entities with different mandates. AthenaBio is based on a thesis that took four years to form: what’s the biggest unlock in this space? I fully believe it’s data.

We’ll get to AthenaBio, but first, for people who are not familiar with this term, what is a DAO? Why did you choose it, what has AthenaDAO accomplished, and why create a more traditional structure?

Clubhouse plays a role again. During the pandemic, we had this huge crypto rally and the NFT craze. People were awash with cash, I guess because of those government checks. They were trading JPEGs of rocks for millions of dollars.

I’m curious about new technology, and I thought, “This is insane. These rocks are so useless.” I understood the people selling them and pitching them as the biggest game changer in the world. I could see how people were ascribing value to them, and it was interesting to watch that mania and hype. I got the sellers’ side. The consumer side was more interesting: “Wow, these people are totally going for it.”

Through longevity, I discovered VitaDAO – the first longevity DAO [decentralized autonomous organization] – as it was launching. The idea was to use blockchain to fund science. You create a token, and people buy it for governance rights, to vote on the science and join the community.

I joined early, stepped away for my own project, then came back. I got more involved because I was talking to Jennifer Garrison about funding research for her organization. I tried presenting the project within VitaDAO.

VitaDAO had a very successful launch. They had what I considered the god of longevity, Aubrey de Grey, and the god of crypto, Vitalik Buterin, together on YouTube. Everybody was at home watching.

All the stars aligned. Literal stars.

Oh my God, all the stars aligned. The token auction brought in millions and millions of dollars.

But no one was interested in funding women’s health or ovarian aging. Then I was asked to MC a DeSci conference. I met the team behind Molecule, who launched VitaDAO, who wanted to do other DAOs, and other women and technologists interested in the space.

Coming back to what a DAO is: you can say it’s a group with a shared mission. You form an organization, figure out how to run it, and go into the market with a governance token. We have an ATH token. Our mission was funding translational research in women’s health: something from a lab that could become a diagnostic, drug, or therapeutic.

We funded projects from $50,000 up to, I guess, $300,000. We ran four cohorts, all around ovarian and reproductive health. Eventually, we could address every kind of condition in women’s health, but those calls for submissions need to be focused.

We funded $1.5 million in research across seven labs, twenty fellowships, and five or six academic conferences, alongside initiatives bringing attention to female researchers and women in biotech. Our big validation moment came this year when we were featured in TIME’s longevity issue.

We supported a company spinning out of an academic lab. Three IP research projects we funded are moving through the regular biotech pipeline and have successfully proven their thesis and theory.

But science takes time and money, and crypto’s timelines don’t work with science’s timelines. With AI, there’s an overemphasis on engineering problems that can be proven fast. You can generate data quickly for those engineering problems. But researchers doing experiments can’t just produce results on demand. Hard scientific discovery for a new molecule or target validation takes time and a lot of capital.

So, what is AthenaBio all about?

Our five-year mandate is to model, measure, and aggregate ovarian aging data, creating robust datasets for the era of AI. It’s a specific end goal: what we’re going to achieve with this capital within a certain period, rather than, “Give me the money and let me figure out what to do.” That distinction matters to me.

AthenaDAO was great schooling: building a science and deal-flow team, doing due diligence, managing projects by milestones to get IP. AthenaBio, on the other hand, is a new type of research organization, closer to an Arc Institute or an FRO, a focused research organization.

The difference is that I don’t think moving labs into a centralized location makes sense here. Most focused research organizations want to build the structure themselves and bring researchers into one place. But when you imagine the capital allocation, moving labs, setting everything up, and only then getting the work done, we’re going to waste a lot of time and capital.

We’d work with labs across the US and the globe, developing protocols and ways to measure things. A big issue is batch integration and batch correction: figuring out what we can take from each lab and finding standardized endpoints to make the datasets valuable.

In five years, we would have new datasets for research and open science. So, again, t’s not, “Give me the money, and it’ll be fine whether we get something done or not.”

So, data collection that’s decentralized but standardized?

Yes, though I don’t want “decentralized” to make it sound like crypto. It’s open science.

Multiple labs working with the same standards and endpoints?

One thing I know is lacking – and here I’ll go back to my fashion life – is something like Pantone. It was our biggest license when we made cases and cables.

I met the founder’s daughter. Her father used to be a paint salesman, I think, and met people who had developed a way of coding colors. You didn’t have to say, “The red that’s a little more white.”

Imagine working with China, LA, New York, and Paris and saying, “Give me the red,” without a code. That’s how the world of paint and color was. Pantone was a genius idea. Now everybody in the creative field has these Pantone books so you can specify exactly what you mean.

We haven’t standardized data as well for our field. We need to know which decisions can’t be made today in ovarian biology, and what’s the failure point. There’s also a crucial lack of sex-specific information. We need to collect more of it and make it available for research.

How has female health been overlooked by medicine and healthcare systems, and where are we today?

It’s only been 30 years since women were mandated into clinical trials. We’re missing a lot of sex-specific information.

We have to look beyond discrimination, too. There are horrible drug development stories where information wasn’t taken into account, causing deaths or birth defects.

Because of female reproduction, clinical research in women became more expensive and difficult. Excluding women optimized the budgets. It starts with mice: female mice are more expensive because they have fertility cycles. With women, you have to be mindful of repercussions like infertility or birth defects.

That created a bias toward excluding females, but women are not men who are 25% smaller. Having ovaries changes everything. It’s also an organ that stops working within our lifetime.

And it orchestrates much of female biology. I don’t think men have anything comparable in its overall impact.

No. Women’s bodies are still a battlefield. Women don’t have full bodily autonomy, to different degrees across the globe. Our reproductive system is weirdly overregulated or not regulated. It’s taboo. People confuse the ovaries’ function with reproduction, when they regulate so much else.

Then there’s who makes decisions in academia. It’s only been maybe 30 or 40 years that academics have become more varied. I’m not saying men don’t study female health, but decision makers have mostly been men. If it’s not a problem you face, why think of it?

Your thesis describes the ovary as a uniquely high-leverage organ and one of the least understood. Could studying its earlier aging give us insights into aging in both sexes?

Five or six years ago, I think, Jennifer Garrison started the Global Consortium for Reproductive Longevity and Equality (GCRLE), which she’s since left. She was the first person I heard advocating so concretely for the ovary as a way to study aging. She did the rounds in longevity many years ago.

For certain aspects of human aging, a longitudinal study would take 70 or 80 years. With the ovary, you have a lifespan of 15, 25, 30, 35 years. It’s a great organ to study longitudinally. Maybe others said it before, but Jennifer was the first I heard really pushing this message.

Studying ovaries would have benefits beyond female health. It could also ultimately reveal things about males. That would be an unlock for the longevity space. Take cellular reprogramming: why don’t we try ovaries first? We could figure it out faster.

That’s a good candidate, I’d say.

In the last New York Times article about Altos Labs, the CEO, Hal Barron, mentioned ovaries. He didn’t say they’re doing it, but I posted the quote, thinking, “Oh my God, I hope they are.” Vittorio Sebastiano and I have talked a lot about this. I’m always trying to get funding so he can do the research.

Sexual dimorphism is the elephant in the room in longevity. Male and female aging are so different, including how geroprotectors work, yet that often gets swept under the rug. What’s your view?

Alzheimer’s is a clear example. More women have it than men, but we’re probably not studying it in women as much as we should.

Then, there are hormones. This factory works within you for years, shaping how your body works. When those hormones aren’t there, it causes havoc. Men have their own problems with testosterone and andropause, but there’s a bigger loss o the female side.

Women also metabolize many drugs differently. Clinical trials have to account for that. Not studying sex-specific differences is constantly to the detriment of bringing things to market.

Turning to AI and advocacy: your whitepaper leans heavily on AI. We probably need it to solve aging’s immense complexity. Given public attitudes ranging from legitimate concerns to demonization, could longevity do more to make that case?

I think AI will do great things. I also think we’re overestimating what it can do, both bad and good.

A lot is at play over who wins: the US versus China, new companies versus the two huge companies that already exist. I think AI is a net positive, and the train has left the station.

I like regulation within limits. This is why I don’t think the FDA sucks, by the way. Could it be better? Yes, but it isn’t solely responsible for where we are in drug discovery. With AI, if we regulate new companies coming in, how will we get innovation? There has to be give and take.

That’s why we’re building our thesis around AI. How will you cure ovarian cancer without researching the fundamental biology, or even having datasets to run models that could find treatments?

My point is that saying AI could develop drugs doesn’t sound convincing enough when the survival of the species is on the other side of the argument. Saying that probably only AI could cure aging might be more convincing. Should we be more vocal about it?

I don’t know if that will work. They say AI will cure cancer because people care about cancer. They don’t care about aging or ovaries.

I don’t make the rules. We need to be realistic. Cancer touches everyone: men, women, dogs. It’s multispecies, genderless. We’ve all lost friends or family to it; some of us have experienced it.

Dementia scares us too, but that’s later in life. Some of us have experienced cancer ourselves, some haven’t, but it touches all our lives. People know it can happen at any stage, from childhood onward. But when it comes to aging, many people say, “Oh my God, no, don’t cure aging.”

That’s basically longevity’s central PR problem.

You have to meet people where they are. Sometimes our field goes to a place people can’t relate to.

In my almost seven years in longevity advocacy, I don’t think we’ve moved the needle much on that.

If anything, it’s moved to wellness, which I find even more dangerous.

Working for a longevity nonprofit, I know how hard fundraising is. Any insights into doing it right? Has the situation improved or worsened?

Ask me in six months. I’ve worked in other fields. I feel like I’ve sold things my entire life. I’ve never found a more complicated, challenging area than women’s health.

The barriers to capital are fascinating. People throw money at other areas of biotech, including philanthropic money. Our job is figuring out what will make someone give you money. For me now, it’s more of a numbers game: trying to meet everyone and anyone who could help with this mission. Every day, we’re figuring out what those levers are.

For reasons that I don’t entirely understand, longevity in general is hard to fundraise for.

And yet, women’s health is a thousand times harder. Longevity has the Brian Armstrongs, people putting their capital or image into it. Vitalik gave a lot. Nobody in crypto has given that kind of money to female health.

You could say we keep hitting the glass ceiling. It illustrates the lack of women among the richest and most powerful people.

People always say, “There’s Melinda Gates.” That’s one woman. Longevity has Jeff Bezos with Altos, Peter Thiel, so many billionaires. Jeff Bezos’s ex-wife gave millions to many things, but nothing I could concretely point to in research.

My call to action is to please let people know we are doing concrete work to address the problem, we have a successful proof of concept on deploying capital and due diligence, we are not just writing or figuring out what is needed, we know and only need the partners and capital that can support this.

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 ethical journalism and sustains our future.
Cilia on a neuron

How Some Neuronal Cilia May Affect the Whole Body

A team of researchers has written a paper with a surprising finding: that many of the benefits of caloric restriction and increased NAD+ may be due to their effects on the cilia of hypothalamic neurons.

Neuronal cilia have a relationship to overall health

To interact with their environment and maintain internal balance, many cells, including hypothalamic neurons, have primary cilia on their external surfaces [1]. Genetic disorders that lead to diabetes and other metabolic issues include ciliary dysfunction among their symptoms, and this dysfunction appears to play a causative role [2]. Impairing ciliary function in adult mice leads to similar metabolic disorders [3].

As cilia and the maintenance process of autophagy are connected [4], and long-lived neurons require functional autophagy to stay alive [5], ciliary health in these cells is critical. Unfortunately, the cilia of neurons shorten with age [6]. This research focuses on the previously undocumented relationship of cilia to NAD+, which has been linked to autophagy through its connection to SIRT1 [7].

SIRT1, NAD+, and cilia

This paper’s first finding was unsurprising: both cilia length and NAD+ decline in the hypothalamus between 3 and 24 months of age in mice. A further experiment found that there is a causative effect, as culturing hypothalamic neurons in vitro and depleting NAD+ from them using FK866 significantly shortened the length of these cells’ cilia, although it did not affect the generation of cilia. Increasing NAD+ in hypothalamic neurons in vitro directly through its precursors lengthened cilia, and suppressing the NAD+ consumer CD38 was even more effective in this. Further experiments found that this affects retinal pigment epithelial cells, and experiments with depleting and repleting NAD+ in 3-month-old mice confirmed its causative relationship to ciliary length in hypothalamic neurons in vivo.

The researchers then looked into the impact of SIRT1. Overexpressing normal SIRT1 in hypothalamic neurons had similar effects to suppressing CD38 in terms of lengthening cilia, and suppressing SIRT1 significantly decreased the effects of increased NAD+. This was found to be due to a specific deacetylase in SIRT1; abnormal SIRT1 that lacked this deacetylase had no effect, and suppressing SIRT1 deacetylase activity also neutralized the effects of increasing NAD+.

An RNA analysis provided more information about these effects. Upregulating SIRT1 also upregulated several genes that are related to ciliary length, and increasing NAD+ through NMN upregulated a few of these genes as well. Roughly a decade ago, this team found that leptin increases RFX1, which is linked to ciliary growth; in this study, the team found that SIRT1 increases the effectiveness on RFX1 through deacetylation. The team also found a connection to autophagy; knocking down a key autophagy-related gene blunted the effects of SIRT1 on ciliary length.

A core causative role

The researchers found that the cilia play a fundamental, causative role in this relationship. Directly suppressing genes that are related to ciliary growth through silencing RNA also suppressed the beneficial effects of NAD+ on autophagy. A protein that appears in the cilia, CHMP4B, was found to be a core part of this relationship; when NAD+ was depleted, this protein stopped appearing in the cilia where it normally does and instead travels to the lysosomes. Using a toxin to injure lysosomal membranes caused CHMP4B to appear there as well. Further work confirmed this conclusion: cilia contain CHMP4B, which returns to lysosomes to maintain their integrity, but NAD+ depletion harms lysosomes and depletes cilia of this protein.

Caloric restriction, which increases NAD+, was found to have similar effects as direct NAD+ interventions in vivo. 24-month-old mice were put on a caloric restriction regimen, and some of them were given silencing RNA against a key ciliary growth gene in the hypothalamus. While calorically restricted aged mice without this silencing RNA had metabolic measurements that were more akin to those of young mice, aged mice with this silencing RNA had some adipose tissue measurements that suggested that they had never been given caloric restriction even though they were. This, therefore, demonstrates that “hypothalamic primary cilia are required for the CR–induced improvements in aging–associated metabolic phenotypes.”

Cilia metabolic effects

This study’s findings are rather striking, as they point to very specific parts of very specific neurons as being fundamental, causative actors in a commonplace longevity intervention. Further work should be done to confirm these findings and determine whether or not there may be interventions that can directly engage the cilia in the hypothalamus in order to treat metabolic disorders.

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 ethical journalism and sustains our future.

Literature

[1] Singla, V., & Reiter, J. F. (2006). The primary cilium as the cell’s antenna: signaling at a sensory organelle. science, 313(5787), 629-633.

[2] Lee, C. H., Kang, G. M., & Kim, M. S. (2022). Mechanisms of weight control by primary cilia. Molecules and cells, 45(4), 169-176.

[3] Davenport, J. R., Watts, A. J., Roper, V. C., Croyle, M. J., van Groen, T., Wyss, J. M., … & Yoder, B. K. (2007). Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Current Biology, 17(18), 1586-1594.

[4] Orhon, I., Dupont, N., Pampliega, O., Cuervo, A. M., & Codogno, P. (2015). Autophagy and regulation of cilia function and assembly. Cell Death & Differentiation, 22(3), 389-397.

[5] Rubinsztein, D. C., DiFiglia, M., Heintz, N., Nixon, R. A., Qin, Z. H., Ravikumar, B., … & Tolkovsky, A. (2005). Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy, 1(1), 11-22.

[6] Oya, M., Miyasaka, Y., Nakamura, Y., Tanaka, M., Suganami, T., Mashimo, T., & Nakamura, K. (2024). Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia. Cell Metabolism, 36(5), 1044-1058.

[7] Lee, I. H., Cao, L., Mostoslavsky, R., Lombard, D. B., Liu, J., Bruns, N. E., … & Finkel, T. (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences, 105(9), 3374-3379.

[8] Kang, G. M., Han, Y. M., Ko, H. W., Kim, J., Oh, B. C., Kwon, I., & Kim, M. S. (2015). Leptin elongates hypothalamic neuronal cilia via transcriptional regulation and actin destabilization. Journal of Biological Chemistry, 290(29), 18146-18155.

CT Scan Robot

AI Extracts Broader Health Insights From Routine CT Scans

A new study suggests that CT scans can provide information about a wide range of conditions, including some not typically diagnosed through imaging. Direct comparison with human radiologists is the next step [1].

Getting more from a scan

A CT scan’s goal is usually to answer a concrete clinical question, such as what is causing abdominal pain or whether a suspected tumor is there. However, the images also capture other tissues and organs. The amount of information in a scan greatly exceeds what any radiologist can possibly register and may point to unrelated and yet undiagnosed conditions. A new study from the University of Pennsylvania, published in npj Digital Medicine, describes an AI model that can glean such clues, raise alarms, and assess future risks.

The authors developed Percival, a vision-language model (VLM) trained on CT images and their accompanying radiology reports. The model was trained on more than 400,000 CT image volumes paired with radiology reports from 52,000 participants. These came from the Penn Medicine BioBank and included different anatomical regions, scanner manufacturers, and imaging protocols, with and without contrast.

The model, which uses 86 million parameters, was trained to match images to their corresponding reports. It produces a numerical representation of each scan (an embedding) that encodes patterns it learned from the images.

Signal detected

Principal component analysis showed that the embeddings reflected differences in patients’ age, sex, and body size. This served as a preliminary check that the model captures meaningful patient characteristics. However, associations with blood pressure, pulse, oxygen saturation, and respiratory rate were weak.

The researchers then tested associations between the embeddings and dozens of types of laboratory measurements, taken within 60 days of imaging. They found significant associations involving 35 measurements (corrected for multiple comparisons), including markers related to kidney function, liver function, glucose and lipid metabolism, blood-cell counts, and inflammation.

This suggested that the scans contain broader physiological information. However, when the researchers tried estimating lab values directly, performance was largely weak. Only some measurements showed predictive power, including albumin, hemoglobin, and creatinine.

The researchers then asked whether the embeddings corresponded to diagnoses across multiple organ systems. They found associations with 351 diagnosis categories, spanning cardiovascular, respiratory, cancer, metabolic, and other conditions, documented or diagnosed around the time of the scan. They also found that some image patterns were associated with a greater number of diagnoses recorded after imaging (“future disease burden”).

After establishing these broad associations, the researchers trained disease-specific classifiers to distinguish people with and without recorded diagnoses. They compared Percival with CT-FM, an AI model trained using images without paired reports, which Percival outperformed. The results were the strongest for atrial fibrillation, coronary atherosclerosis, heart failure, and pancreatic cancer. For some of those conditions, such as atrial fibrillation, primary diagnosis does not ordinarily rely on CT.

Future disease prediction

The ultimate test was predicting later diagnoses. Percival competed with an image-only AI model, as well as with predictions that used organ measurements or age and sex, outperforming all of them. Top results were achieved for heart failure, cirrhosis, and acute kidney failure.

“Percival can help identify unrecognized disease, predict future progression, and anticipate major cardiovascular and liver complications,” said co-author Charles Kahn, a professor of radiology. “Because many patients already have substantial heart or metabolic disease when they enter specialty care, routine imaging may provide an opportunity for earlier recognition and intervention.”

However, a later recorded diagnosis does not necessarily mean that a disease developed after imaging. The researchers did not exclude diagnoses made shortly afterwards. Some predictions may therefore relate to an existing condition that had not yet been formally documented. It is a valuable capability but different from forecasting disease years before onset.

“Our teams have developed something that learns broadly from imaging data and uncovers connections between scans, lab values, people’s physiology, and clinical outcomes to potentially give more accurate assessments of health or even ring alarm bells early,” said senior author Walter Witschey, an associate professor of radiology and the associate vice chair of research IT. “This is work that points toward a future in which medical imaging becomes a foundation for more personalized and proactive health care.”

The study suggests that there is potential value in vision-language models that can combine several types of data from the patient’s health records. However, no direct comparison with human radiologists was made, so the study does not establish that Percival is better at diagnosing the conditions a CT scan was ordered to investigate.

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 ethical journalism and sustains our future.

Literature

[1] Beeche, C. A., Kim, J., Tavolinejad, H., Zhao, B., Dong, J., Sharma, R., … & Penn Medicine Biobank. (2026). Generalizable CT vision-language modeling for population health and disease risk. npj Digital Medicine.

Endothelial cells

An RNA Regulator Mitigates Senescence in Blood Vessels

Researchers publishing in Aging Cell have found that the regulatory protein MTR4 fights DNA damage in the blood vessel lining but decreases with aging.

Vulnerable by nature

This paper begins by noting the properties, and aging, of vascular endothelial cells (VECs), which line the blood vessels and govern their permeability [1]. As these cells are directly exposed to inflammatory factors and other blood-based stresses, they are some of the most rapidly aging cells in the human body [2]. When these cells become senescent, they excrete harmful senescence-related compounds (the SASP) directly into the bloodstream, and senescent VECs are connected to a wide variety of cardiovascular and other diseases, including hypertension and diabetes [3].

Their connection to multiple diseases, and bloodstream availability, make them an “attractive target” for interventions. However, killing senescent VECs off en masse through senolytics may be a bad idea, as one experiment found that this practice can promote fibrosis and shorten lifespan in mice [4] while another found that it can make hypertension worse [5].

Therefore, these researchers focus on methods to bolster these cells’ resilience, which was found to be a sound approach in previous experiments [6, 7]. Most previous work has focused on well-known factors such as Klotho and sirtuins, but these researchers chose a different target: MTR4, an RNA helicase that plays crucial roles in RNA maintenance [8] and the cell cycle [9]. While impeding part of its function has been found to lead to senescence [10], its true impact as a senescence regulator was not previously examined.

Expected changes with age

These researchers first used VECs derived from the human umbilical cord (HUVECs) and drove them senescent through genotoxins, oxidative stress, or replication. In all of these cells, MTR4 significantly declined. Quiescent stem cells, which had no stimulus to divide but were not senescent, did not exhibit a similar decline in MTR4. Similar results were found in mice; 3-month-old mice exhibited significantly higher levels of MTR4 than 20-month-old mice in multiple organs, including the heart, liver, and aorta.

The study then sought to ascertain a cause-and-effect relationship by using silencing RNA to turn off MTR4 in proliferating HUVECs. Markers of cellular senescence in these cells substantially increased, including SA-β-gal, while SASP factor expression increased as well. The inverse experiment also yielded results: replicatively senescent HUVECs that overexpressed MTR4 partially reversed such senescent phenotypes, including broad reductions in SASP expression.

The first link in a chain

An RNA sequencing analysis confirmed these results, although most of these results were ascertained to be downstream of its true effects. The authors identified 92 potentially interacting proteins, used the GenAge database to discover five particularly notable ones, and found that it physically interacts with BUB3 in a way that suppresses cellular senescence; directly overexpressing BUB3 had similar effects to directly overexpressing MTR4. Generating a mutant version of MTR4 that could not interact with BUB3 had no beneficial effects, and MTR4 was found to physically stabilize BUB3.

The researchers found another link in the chain: BUBR1, which itself is stabilized by BUB3. BUBR1 is a core spindle assembly checkpoint kinase that protects DNA during division. The researchers hold that this protection is the core reason behind the antisenescence effects of MTR4.

However, interestingly, RNA expression of MTR4 is increased rather than decreased in senescent cells. The reason that its protein levels decrease, therefore, is accelerated decomposition. The researchers found that this was being done through the ubiquitin-proteasome system rather than autophagic processes. This ubiquitination was found to be caused by an increase in another protein, SYVN1. The researchers even identified the particular lysine on this protein, K638, that allows for this ubiquitination.

Strong effects on blood vessels

The researchers then turned to mice and found significant results on their physiology and behavior after exposure to adeno-associated viruses (AAVs) that influence Mtr4. Aged mice that overexpressed Mtr4 had increased exploratory behavior and better vascular function, while young mice that underexpressed it had reduced exploratory behavior along with vascular dysfunction. Similar results were even found in C. elegans worms; worms that overexpressed mtr-4 lived considerably longer than wild-type worms, approaching the lifespans of well-known longevity mutants in the species, while underexpressing worms had significantly reduced lifespan.

The authors of this paper hold that MTR4 is “a conserved antiaging factor in the vascular endothelium.” While these results are strong, finding treatments that effectively target MTR4 in people will be its own challenge.

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 ethical journalism and sustains our future.

Literature

[1] Augustin, H. G., & Koh, G. Y. (2024). A systems view of the vascular endothelium in health and disease. Cell, 187(18), 4833-4858.

[2] Bloom, S. I., Islam, M. T., Lesniewski, L. A., & Donato, A. J. (2023). Mechanisms and consequences of endothelial cell senescence. Nature Reviews Cardiology, 20(1), 38-51.

[3] Han, Y., & Kim, S. Y. (2023). Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics. Experimental & Molecular Medicine, 55(1), 1-12.

[4] Grosse, L., Wagner, N., Emelyanov, A., Molina, C., Lacas-Gervais, S., Wagner, K. D., & Bulavin, D. V. (2020). Defined p16High senescent cell types are indispensable for mouse healthspan. Cell metabolism, 32(1), 87-99.

[5] Born, E., Lipskaia, L., Breau, M., Houssaini, A., Beaulieu, D., Marcos, E., … & Abid, S. (2023). Eliminating senescent cells can promote pulmonary hypertension development and progression. Circulation, 147(8), 650-666.

[6] Chivite, I., Monelli, E., Munar-Gelabert, M., Gómez-Valadés, A. G., Alvarado-Diaz, A., Pozo, M., … & Claret, M. (2026). Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice. Cell Metabolism, 38(3), 546-564.

[7] Pang, J., Pan, L., Shen, W., Yi, G., Kong, X., Zhang, H., … & Zhang, Y. (2025). Endothelial LRRC8A delays vascular ageing in natural and accelerated ageing mouse models. Cardiovascular Research, 121(16), 2549-2564.

[8] Olsen, K. J., & Johnson, S. J. (2021). Mtr4 RNA helicase structures and interactions. Biological chemistry, 402(5), 605-616.

[9] Zhang, L., Wang, J., Tang, Z., Lin, Z., Su, R., Hu, N., … & Cheng, H. (2025). The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation. Nature Communications, 16(1), 2605.

[10] Han, X., Xing, L., Hong, Y., Zhang, X., Hao, B., Lu, J. Y., … & Shen, X. (2024). Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence. Cell Stem Cell, 31(5), 694-716.

Bone structure

Blocking STING Helps Preserve Bone in Aging Mice

A new study links STING-mediated signals from marrow fat cells to inflammation and declining NAD⁺ levels in bone-forming cells. Interrupting this pathway helped preserve aging bone [1].

Making old bones

Our bones live a complex life, as they are constantly remodeled: cells called osteoclasts break down existing bone, while osteoblasts build new bone. Osteoblasts arise from bone marrow mesenchymal stem cells (BMSCs), which can also produce fat cells. With aging, bone marrow accumulates more fat, becomes more inflammatory, and supports bone formation less effectively [2]. However, scientists do not fully understand how this process works yet.

A new study by Chinese researchers, published in Advanced Science, focused on macrophages, a type of immune cell. In particular, they investigated cGAS–STING, an immune signaling pathway activated by DNA appearing in the cell’s cytoplasm outside its usual compartments. This mechanism helps detect viral or bacterial DNA, but with age, it starts to misfire, triggered by stimuli such as leaked mitochondrial DNA [3]. The enzyme cGAS detects this misplaced DNA and produces the messenger molecule cGAMP, which activates STING and downstream inflammatory signaling.

A STING operation

The researchers asked whether STING’s net effect changes with age, what activates it in aging marrow, and how activated macrophages affect neighboring bone-forming cells. First, they compared bone marrow from mice aged 3, 10, 18, and 24 months and found progressively greater activation of the cGAS–STING pathway. This included more DNA in the cytoplasm, more cGAMP, and increased phosphorylation (a sign of activation) of STING and downstream signaling proteins.

They then compared different marrow cell populations. Macrophages had the highest baseline expression of the Sting gene, and their STING activation increased with age. This established macrophages as a plausible intervention target, but it was still unclear whether their STING activity was in itself harmful or a response to other damage.

The authors used a macrophage-specific viral vector to silence Sting from 12 to 18 months of age in mice. This significantly preserved bone density and structure. It also increased measures of new bone deposition and reduced marrow fat-cell numbers.

To understand what in aging marrow activates macrophage STING, the researchers investigated interactions between cells. Old macrophages impaired the ability of young BMSCs to develop into bone-forming cells, whereas old macrophages lacking STING were less harmful.

Next, the team examined potential upstream triggers. Exposure to bacterial lipopolysaccharide (LPS), a component of bacterial membranes, activated STING in macrophages, as expected. Old mice also had more endotoxin in blood and marrow, which can contribute to increased STING levels.

Inflammation and mitochondrial damage, combined

The authors then focused on marrow fat cells. Secretions from old marrow fat cells activated macrophage STING both in culture and when injected into young mice’s marrow. Co-culturing old fat cells with young macrophages produced a similar response.

44 secreted proteins elevated in bone marrow with age. The researchers singled out one of them: DPP4. Of all the tested marrow cell types, fat cells released substantially more soluble DPP4, and old fat cells released more than young ones.

Injecting DPP4 into young mice’s marrow for four weeks worsened bone density and architecture and activated macrophage STING. Conversely, reducing Dpp4 expression in marrow fat cells significantly improved one measure of bone structure health (spacing between trabeculae).

However, DPP4 alone did not significantly activate STING but, rather, strengthened its activation when combined with old marrow fluid. Thus, DPP4 appeared to contribute to an inflammatory environment rather than act as a sufficient trigger by itself.

The authors tested several possible receptors for DPP4 and focused on TLR4, a cell-surface receptor involved in innate immune responses. Blocking TLR4 reduced STING activation, and protein-interaction experiments supported direct binding between DPP4 and TLR4.

Importantly, old macrophages contained more mitochondrial DNA outside their mitochondria. Reducing mitochondrial DNA with low-dose ethidium bromide partially reduced STING activation. Old macrophages also showed more signs of mitochondrial stress.

The researchers suggest that external inflammatory signals, including DPP4-associated TLR4 signaling, “cooperate” with internal mitochondrial damage to sustain STING activity.

The NAD⁺ connection

The researchers also found that macrophage NAD⁺ levels declined with age, while NAD⁺-degrading activity increased. Experimentally activating the pathway lowered macrophage NAD⁺ but suppressing cGAS or STING counteracted these changes. Further experiments suggested that STING signaling increases production of the enzyme CD38, which degrades NAD⁺.

How could an enzyme in macrophages reduce NAD⁺ inside BMSCs? Further experiments suggested that CD38 that sits on the cell surface degrades extracellular NAD⁺ and its precursor NMN, potentially limiting the supply available to nearby cells.

Old BMSCs had impaired mitochondrial function and lower production of the cellular energy currency ATP. NMN supplementation partially rescued these metrics but to a reduced degree in old or artificially activated macrophages. Suppressing cGAS or STING in the macrophages seemed to work as well: macrophages from old mice with Sting or Cd38 knockout had better mitochondrial respiration.

Finally, the team tested a pharmacological intervention: STING inhibitor H-151 combined with NMN supplementation in mice from 12 to 18 months of age. The combination preserved bone density and structure, increased new bone deposition, reduced inflammatory markers, and improved NAD⁺ levels and mitochondrial function in BMSCs.

The researchers used alendronate, an established anti-osteoporosis drug, as a positive control. Improvements in bone structure in the alendronate group were largely similar to the H-151/NMN group.

Among the study’s limitations are its small size and combining two treatments in the intervention experiment. The latter makes it hard to disentangle the effects of STING inhibition from those of NMN supplementation. More research is needed to investigate these interesting findings further.

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 ethical journalism and sustains our future.

Literature

[1] Li, Z., Gao, K., Wang, M., Liang, S., Li, D., Tan, G., Xue, H., Liu, Y., Zhang, P., Xu, Z., Cheng, W., Wang, Y., & Li, N. (2026). Bone marrow macrophage STING signaling is a direct nexus linking marrow adipose expansion to NAD⁺ depletion and osteogenic decline in skeletal aging. Advanced Science.

[2] Aaron, N., Costa, S., Rosen, C. J., & Qiang, L. (2022). The implications of bone marrow adipose tissue on inflammaging. Frontiers in Endocrinology, 13, 853765.

[3] Gulen, M. F., Samson, N., Keller, A., Schwabenland, M., Liu, C., Glück, S., … & Ablasser, A. (2023). cGAS–STING drives ageing-related inflammation and neurodegeneration. Nature, 620(7973), 374-380.

Mechanical cell

Making SIRT1 and NAD+ Therapies Work in People

Reviewers publishing in Biology have elucidated SIRT1 functional reserve as an aspect of aging, describing how its depletion is an upstream cause of age-related disorders at the cellular level and explaining why many prospective therapies that increase SIRT1 and NAD+ have not had promising results.

Managing a dangerous byproduct

Reactive oxygen species (ROS) are necessarily produced as part of basic cellular biology, and under normal conditions, they serve signaling functions [1]. With aging, however, ROS handling becomes dysregulated, leading to their accumulation and thus to age-related cellular dysfunction [2].

The sirtuin SIRT1, which depends on NAD+ to function [3], is very well-known in its utility in managing ROS. However, the simple presence of SIRT1 within a cell does not necessarily mean that it is active, and even if it is active, it may not be meeting the cell’s fluctuating needs. These reviewers, therefore, introduce the concept of SIRT1 functional reserve, a metric intended to “describe the remaining operational flexibility of SIRT1-dependent regulatory processes under a defined stress demand” and thus measure how well a cell can “engage, coordinate, and recover SIRT1-dependent responses”.

As this is intended to be a measurable and experimentally testable metric rather than simply a broad concept, the reviewers largely focused on SIRT1’s relationship to redox reactions and mitochondria; while SIRT1’s use throughout cells should be measured in its analysis, SIRT1 functional reserve does not reflect every use of SIRT1, nor does it measure cellular aging as a whole.

SIRT1 Functional Reserve

Functional reserve is not availability

The reviewers note that measuring total cellular NAD+ may not reflect its complete relationship to SIRT1 functional reserve. NAD+ is spatially located within various parts of a cell and is used and consumed by a variety of processes and molecules such as CD38 [4]. While the various pools that hold NAD+ may be connected, and mitochondria also hold NAD+ [5], there is no guarantee that a cell that is presumably abundant in total NAD+ is delivering enough of it to SIRT1 in a way that properly handles ROS. Similiarly, NAD+ availability does not necessarily reflect SIRT1 prevalence.

SIRT1 also appears as various isoforms, and the v2 and v3 varieties, which accumulate with age, are less functional than the full-length v1 version [6]. Measuring total SIRT1 in a way that does not account for these isoforms, therefore, lacks usefulness in estimating its functional reserve. Additionally, SIRT1 can be modified as a protein by oxidative and other stresses, some of which degrade its capabilities [7] while others enhance them [8].

SIRT1 is used throughout cells

The reviewers note that aging often impairs proper responses and the recovery from such [9]. SIRT1 is a crucial component of these responses, as it directly interacts with energy-sensing pathways [10]. Measuring this interaction, however, can be counterintuitive; for example, during high-intensity interval exercise, SIRT1 activity increased while its total level decreased [11]. Furthermore, the strength of a stress response may or may not correspond to its resolution; a strong response does not signify full recovery, and a weaker response may signify that the cell has handled the situation with less effort [12].

The reviewers also add that repeated stress, a well-known precursor of cellular decline, may alter SIRT1 dynamics [13] but does not necessarily result in a loss of SIRT1 function. Additionally, SIRT1 helps to regulate the heat shock protein HSF1 [14], which aid in proteostasis, while other heat shock proteins regulate SIRT1 [15]. Disruption of this, therefore, leads to a harmful feedback loop: the very machinery that is supposed to regulate proteostasis is harmed by the lack of proteostasis regulation. SIRT1 also regulates proteostasis in mitochondria [16].

SIRT1 is often part of a greater regulatory framework rather than an independent factor. Therefore, the reviewers warn that “enhancement of SIRT1 activity may yield progressively smaller benefits if other determinants of adaptation become limiting,” which may explain some weaker results seen in studies aimed at SIRT1 enhancement [17]. Such other causes need to be separated in order to properly measure SIRT1 functional reserve.

From function to dysfunction

This review discusses the adaptive-to-maladaptive transition within cells, which is a gradual process that does not have a clear line. During chronic stress, cells compensate in ways that involve either the constant use of compensatory mechanisms or altering their structure. SIRT1 is involved in both cases, although in different ways; it can be engaged in ways that involve stress tolerance, and its function can be affected by cellular changes, particularly senescence. According to the reviewers, therefore, “the same level of SIRT1 protein or activity may not produce equivalent functional output under different cellular conditions.” They propose including stress history as part of estimating the functional reserve of SIRT1.

The species and cell involved also determine the role of SIRT1. Some experiments show a straightforward relationship: increasing oxidative stress in various human cells depletes SIRT1. Others, however, such as caloric restriction and exercise in mice, change SIRT1 in a tissue-specific way. Neural stem cells are particularly vulnerable to perturbations in SIRT1 [18]. Therefore, systemic measurements of SIRT1 and/or NAD+ may not properly reflect its use or influence in cells, and its functional reserve must be measured with cell type in mind.

Towards the clinic

This review provides heavily substantiated explanations of why commonly tested methods, such as increasing SIRT1 and NAD+, along with directly targeting oxidative stress at the mitochondrial level through MitoQ [19], have had mixed results. However, this paper also acknowledges that its own framework requires experimental validation. They propose experiments in which SIRT1 functional reserve is measured by analyzing its forms and locations within the cell along with the locations of NAD+, ROS measurements, and various biomarkers of cellular health and inflammation.

Of course, the “main translational question is whether changes in SIRT1-dependent adaptive capacity can be linked to meaningful functional outcomes in humans.” The amount of work needed to verify and validate this approach, and so move towards SIRT1 and NAD+ therapies with a higher chance of working in people, will be substantial.

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 ethical journalism and sustains our future.

Literature

[1] Sies, H., Mailloux, R. J., & Jakob, U. (2024). Fundamentals of redox regulation in biology. Nature Reviews Molecular Cell Biology, 25(9), 701-719.

[2] Atayik, M. C., & Çakatay, U. (2023). Redox signaling and modulation in ageing. Biogerontology, 24(5), 603-608.

[3] Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature reviews Molecular cell biology, 22(2), 119-141.

[4] Chini, C. C., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., … & Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nature metabolism, 2(11), 1284-1304.

[5] Høyland, L. E., VanLinden, M. R., Niere, M., Strømland, Ø., Sharma, S., Dietze, J., … & Ziegler, M. (2024). Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+. Nature Metabolism, 6(12), 2319-2337.

[6] Patyal, P., Ameer, F. S., Verma, A., Zhang, X., Azhar, G., Shrivastava, J., … & Wei, J. Y. (2024). The role of Sirtuin-1 isoforms in regulating mitochondrial function. Current Issues in Molecular Biology, 46(8), 8835-8851.

[7] Caito, S., Rajendrasozhan, S., Cook, S., Chung, S., Yao, H., Friedman, A. E., … & Rahman, I. (2010). SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress. The FASEB Journal, 24(9), 3145.

[8] Han, C., Gu, Y., Shan, H., Mi, W., Sun, J., Shi, M., … & Yu, W. (2017). O-GlcNAcylation of SIRT1 enhances its deacetylase activity and promotes cytoprotection under stress. Nature communications, 8(1), 1491.

[9] Lomeli, N., Bota, D. A., & Davies, K. J. (2017). Diminished stress resistance and defective adaptive homeostasis in age-related diseases. Clinical Science, 131(21), 2573-2599.

[10] Cantó, C., Jiang, L. Q., Deshmukh, A. S., Mataki, C., Coste, A., Lagouge, M., … & Auwerx, J. (2010). Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell metabolism, 11(3), 213-219.

[11] Gurd, B. J., Perry, C. G., Heigenhauser, G. J., Spriet, L. L., & Bonen, A. (2010). High-intensity interval training increases SIRT1 activity in human skeletal muscle. Applied Physiology, Nutrition, and Metabolism, 35(3), 350-357.

[12] Lamech, L. T., & Haynes, C. M. (2015). The unpredictability of prolonged activation of stress response pathways. The Journal of cell biology, 209(6), 781

[13] Zhang, J., Wang, H., Slotabec, L., Cheng, F., Tan, Y., & Li, J. (2023). Alterations of SIRT1/SIRT3 subcellular distribution in aging undermine cardiometabolic homeostasis during ischemia and reperfusion. Aging Cell, 22(9), e13930.

[14] Westerheide, S. D., Anckar, J., Stevens Jr, S. M., Sistonen, L., & Morimoto, R. I. (2009). Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science, 323(5917), 1063-1066.

[15] Białopiotrowicz-Data, E., Noyszewska-Kania, M., Jabłońska, E., Sewastianik, T., Komar, D., Dębek, S., … & Juszczyński, P. (2023). SIRT1 and HSP90α feed-forward circuit safeguards chromosome segregation integrity in diffuse large B cell lymphomas. Cell Death & Disease, 14(10), 667.

[16] Chen, Q., Chang, Y. L., Hung, M. W., Lee, P. L., Hsin, C., & Lin, Y. F. (2026). Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish. Frontiers in Cell and Developmental Biology, 14, 1761278.

[17] Alcendor, R. R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., … & Sadoshima, J. (2007). Sirt1 regulates aging and resistance to oxidative stress in the heart. Circulation research, 100(10), 1512-1521.

[18] Wang, G., Wang, F., Ren, J., Qiu, Y., Zhang, W., Gao, S., … & Xu, J. (2018). SIRT1 involved in the regulation of alternative splicing affects the DNA damage response in neural stem cells. Cellular Physiology and Biochemistry, 48(2), 657-669.

[19] Broome, S. C., Whitfield, J., Janssens, K., & Hawley, J. A. (2025). MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals. Redox Biology, 103927.

Proteins in the brain

Menopausal Serum Protein Changes May Predict Brain Health

A recent analysis of serum protein changes identified 16 proteins related to inflammatory, synaptic, metabolic, and Alzheimer’s disease processes whose levels change during the menopausal transition [1]. These changes were linked to cognitive health later in life.

The time for interventions

Menopause is mostly known as a stage that marks the end of female reproduction, but the effects of menopause go beyond the reproductive system and affect many organs and systems, with the impact on the brain being widely discussed and researched. For example, multiple studies have reported that women experience various cognitive difficulties during menopause, such as word-finding or attentional difficulties. A recent review estimated that such problems affect between 26 and 95% of menopausal women [2]. Additionally, different studies suggested that the aging of the hypothalamus plays a causal role in ovarian senescence and menopause induction [3]. These data suggest a strong connection between the brain and menopause, creating a window of opportunity during the menopausal transition for improving brain aging and affecting dementia risk.

“Menopause is a normal physiological process that every person who has ovaries who lives long enough will go through,” said Madeline Wood Alexander, a graduate student at the University of Toronto. “We don’t want it to be viewed as a bad thing, but as an opportunity to better understand and maybe modify the biology of brain aging in women.”

Kaitlin Casaletto, Ph.D., an associate professor at the UCSF Fein Memory and Aging Center and co-senior author of the study, added, “Midlife is a critical window for both men and women where we can really set up the brain to be more resilient or more vulnerable to dementia in later life.” “For women, menopause may be this especially powerful time to intervene.”

Menopause proteomic score

Although many studies suggest a connection between menopause and brain aging, human data remain scarce, limiting the ability to understand the underlying molecular pathways driving these processes.

The researchers of this study began by investigating blood biomarkers associated with spontaneous menopause in healthy midlife women (43-58 years old): 30 premenopausal, 26 perimenopausal, and 24 postmenopausal women, along with 36 age-matched men for comparison.

Comparing serum protein levels (proteomics) showed an increase in 16 proteins in postmenopausal women compared to premenopausal women after adjusting for age. These proteins were related to inflammatory, synaptic, metabolic, and Alzheimer’s disease processes, with inflammatory molecules predominant, consistent with previous studies showing increased systemic inflammation after menopause [4].

Because the cohort used to identify these protein changes was relatively small, they also analyzed data from almost 3,000 women in the UK Biobank. 13 of the 16 proteins identified as showing menopause-stage differences were measured in both cohorts; of those, 9 replicated across cohorts.

The observed changes in synaptic and Alzheimer’s disease blood markers align with previous animal studies showing synaptic plasticity and spine density disruptions [5, 6], along with increases in Aβ and tau positron emission tomography (PET) across menopause [7, 8].

Using those 16 proteins, the researchers created a proteomic score that holistically reflects major menopause-related changes with less data noise. Using this score, they showed that compared to premenopausal women, perimenopausal status was associated with an increase of 1.36 units in menopause scores, and postmenopausal status with a 3.25-unit increase. Importantly, the menopausal stage, rather than chronological age, drove the observed changes.

Hormonal changes and menopausal symptoms

One of the most important changes during menopause is hormonal changes, such as reductions in the ovarian hormones 17β-estradiol and progesterone along with increases in follicle-stimulating hormone (FSH).

In this study, the authors found a positive association between their menopause proteomic score and FSH levels, an inverse association between this score and estradiol levels, and no association with progesterone levels. At a more granular level, they reported that some inflammation-related protein levels were inversely associated with 17β-estradiol, which aligns with the role of estrogens in modulating immune responses [9], while other proteins related to inflammatory, synaptic, metabolic, and Alzheimer’s disease processes were positively associated with FSH.

The authors note that this aligns with previous studies showing that “FSH receptors are expressed abundantly in AD-vulnerable brain regions” and that data from animal models suggest FSH’s role in the development of Alzheimer’s disease, neuroinflammation, and cognitive deficits [10]. In their analysis, the identified proteins were clustered into two separate groups, which suggests that each hormone might be linked to different biological pathways.

Menopause is also widely known as a stage in life when women experience various vasomotor symptoms, such as night sweats or hot flashes, and some of those vasomotor symptoms have been associated with vascular inflammation [11, 12], cardiovascular risk, and Alzheimer’s disease-related brain changes [13]. In this study, the authors analyzed different cohorts for the association between menopausal score and vasomotor symptoms. The results were inconsistent across the cohorts, but some suggested a link between some vasomotor symptoms and menopausal score.

Predicting future cognitive health

Beyond many previously reported links between menopausal changes and brain health, these researchers tested how relevant changes in serum proteins are for later-life cognitive health. They analyzed data from four independent cohorts of older women and found a consistent association between higher (more postmenopausal) baseline menopause scores and worse cognitive health later in life and a higher risk for Alzheimer’s disease dementia, suggesting that changes in certain protein levels during menopause may remain relevant in later decades of life.

“We don’t think that menopause is directly causing dementia,” said Casaletto. “But it’s possible that we may be able to predict a woman’s risk for dementia decades later by the levels of these molecules around menopause.”

While all women will undergo menopause, only a fraction will develop dementia. Molecular signatures during the menopausal transition can provide the earliest signals of future risk of developing the disease.

“We’re identifying molecular shifts in blood, in midlife post-menopausal women, that are also predicting cognition later in life,” said co-senior author Rowan Saloner, Ph.D., assistant professor at the UCSF Fein Memory and Aging Center. “So, we think these molecules are really important markers of both menopause and cognitive 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 ethical journalism and sustains our future.

Literature

[1] Wood Alexander, M., Rabin, J. S., Caunca, M., Iadipaolo, A., Cornelis, L., Warrier, R., Walker, K. A., Miolane, N., Bot, V. A., Wood, B., Oh, H. S., Wyss-Coray, T., Pham, A., Borger, J., Diaz, V., Paolillo, E. W., Kramer, J., Pritschet, L., Taylor, C., Panizzon, M. S., … Casaletto, K. B. (2026). Blood proteomics of menopause map to brain aging and dementia risk. Nature medicine, 10.1038/s41591-026-04648-4. Advance online publication.

[2] Gurvich, C., Spector, A., & Hickey, M. (2026). Advances in understanding of cognitive symptoms during menopause. The Lancet Obstetrics, Gynaecology, & Women’s Health, 2(4), e335–e345.

[3] Bacon, E. R., Mishra, A., Wang, Y., Desai, M. K., Yin, F., & Brinton, R. D. (2019). Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiology of aging, 74, 213–224.

[4] McCarthy, M., & Raval, A. P. (2020). The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease. Journal of neuroinflammation, 17(1), 317.

[5] Hara, Y., Waters, E. M., McEwen, B. S., & Morrison, J. H. (2015). Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. Physiological reviews, 95(3), 785–807.

[6] Russell, J. K., Jones, C. K., & Newhouse, P. A. (2019). The Role of Estrogen in Brain and Cognitive Aging. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 16(3), 649–665.

[7] Buckley, R. F., O’Donnell, A., McGrath, E. R., Jacobs, H. I. L., Lois, C., Satizabal, C. L., Ghosh, S., Rubinstein, Z. B., Murabito, J. M., Sperling, R. A., Johnson, K. A., Seshadri, S., & Beiser, A. S. (2022). Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study. Annals of neurology, 92(1), 11–22.

[8] Rahman, A., Schelbaum, E., Hoffman, K., Diaz, I., Hristov, H., Andrews, R., Jett, S., Jackson, H., Lee, A., Sarva, H., Pahlajani, S., Matthews, D., Dyke, J., de Leon, M. J., Isaacson, R. S., Brinton, R. D., & Mosconi, L. (2020). Sex-driven modifiers of Alzheimer risk: A multimodality brain imaging study. Neurology, 95(2), e166–e178.

[9] Straub R. H. (2007). The complex role of estrogens in inflammation. Endocrine reviews, 28(5), 521–574.

[10] Xiong, J., Kang, S. S., Wang, Z., Liu, X., Kuo, T. C., Korkmaz, F., Padilla, A., Miyashita, S., Chan, P., Zhang, Z., Katsel, P., Burgess, J., Gumerova, A., Ievleva, K., Sant, D., Yu, S. P., Muradova, V., Frolinger, T., Lizneva, D., Iqbal, J., … Ye, K. (2022). FSH blockade improves cognition in mice with Alzheimer’s disease. Nature, 603(7901), 470–476.

[11] Thurston, R. C., El Khoudary, S. R., Sutton-Tyrrell, K., Crandall, C. J., Gold, E., Sternfeld, B., Selzer, F., & Matthews, K. A. (2011). Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation. Menopause (New York, N.Y.), 18(10), 1044–1051.

[12] Bechlioulis, A., Naka, K. K., Kalantaridou, S. N., Kaponis, A., Papanikolaou, O., Vezyraki, P., Kolettis, T. M., Vlahos, A. P., Gartzonika, K., Mavridis, A., & Michalis, L. K. (2012). Increased vascular inflammation in early menopausal women is associated with hot flush severity. The Journal of clinical endocrinology and metabolism, 97(5), E760–E764.

[13] Thurston, R. C., Maki, P., Chang, Y., Wu, M., Aizenstein, H. J., Derby, C. A., & Karikari, T. K. (2024). Menopausal vasomotor symptoms and plasma Alzheimer disease biomarkers. American journal of obstetrics and gynecology, 230(3), 342.e1–342.e8.

Vegan buffet

Low-Fat Vegan Diet Shows Benefits in Type 2 Diabetes

A human trial found that even without caloric restriction, a low-fat, plant-based diet improved blood sugar control, reduced liver fat, and lowered the quantity of advanced glycation end products (AGEs) in the skin [1].

An all-you-can-eat vegan buffet

Type 2 diabetes is an age-related metabolic disorder in which the body becomes less able to regulate blood glucose. Two major problems usually underlie disease onset: tissues respond less strongly to insulin signaling, meaning that they take up less glucose from the bloodstream, and pancreatic beta cells, which produce insulin, become less able to meet the body’s needs.

As with many biological processes, a self-reinforcing loop can develop: insulin resistance increases the demand for insulin, while insufficient secretion allows glucose levels to rise, further impairing beta-cell function. The accumulation of fat surrounding the internal organs (visceral fat) and fat deposited outside its usual storage sites (ectopic fat), such as inside liver and muscle cells, is thought to be a major contributor to this metabolic dysfunction [2].

Dietary interventions for type 2 diabetes usually require reducing caloric intake and can be hard to adhere to. A new clinical trial, led by researchers at the Physicians Committee for Responsible Medicine, in collaboration with the Yale School of Medicine, and published in BMJ Open Diabetes Research & Care, tried a different approach: an all-you-can-eat low-fat plant-based diet. While previous studies have investigated plant-based diets in obesity and diabetes, this is “the first to simultaneously measure liver fat, muscle fat, visceral fat, and tissue advanced glycation end-products (AGEs) in a single plant-based dietary intervention in people with type 2 diabetes,” according to the accompanying press release.

Fewer calories without counting

25 adults with type 2 diabetes began a 16-week low-fat vegan diet, and all but one completed it. They averaged 59 years of age, had an average BMI of about 31, and had lived with diabetes for about 6.6 years. People using insulin, sulfonylureas, or weight-loss medications were excluded, while diabetes medications such as metformin were allowed.

The prescribed diet was based on vegetables, grains, legumes, and fruit, with animal products and added fats completely excluded. Its target composition was approximately 75% carbohydrate, 15% protein, and 10% fat. Participants were told to eat to satiety, without counting calories, and to maintain their exercise habits.

Despite that, participants reported eating about 346 fewer calories per day. Average carbohydrate consumption increased only modestly, from 198 to 259 grams a day; fiber consumption increased almost twofold; total fat consumption dropped by more than three times, and saturated fat consumption by more than five times; and protein consumption decreased only slightly, from 70 to 59 grams a day.

Participants lost 6 kilograms on average, or 6.6% of their starting weight. Fat mass fell by 4.2 kilograms, and visceral fat volume decreased by approximately 290 cm³, from 2,168 to 1,878 cm³. Liver fat decreased substantially, by 33% on average. Some lean mass was lost as well, which is something that future trials may address.

Importantly, these changes did not come from more exercise, as reported physical activity actually decreased. Neither fasting nor post-meal energy expenditure changed significantly, as well as the increase in energy expenditure after eating (the thermic effect of food). Among the 16 metformin users who completed the study, five reduced their dose and two discontinued it. No participant started or increased a glucose-lowering medication.

Better glucose control and less AGEs

The “under the hood” results were impressive as well, with blood glucose control improving substantially. Average fasting glucose fell from 155 mg/dL to 116 mg/dL, fasting insulin from 13.5 µU/mL to 8.8 µU/mL, and harmful LDL cholesterol from 108 mg/dL to 86 mg/dL. HbA1c, a marker of long-term glucose trends, fell from 7.6% to 6.6%, dipping below the usual treatment target of 7% for many adults with diabetes. On the other hand, beneficial HDL cholesterol also fell, from approximately 55 to 47 mg/dL, and triglycerides did not change significantly.

Several metrics suggested that beta cells became more responsive to glucose. Estimated insulin secretion increased at higher glucose concentrations, and rate sensitivity improved: beta cells responded more strongly to the speed at which glucose was rising.

AGEs are compounds formed when sugars react with proteins or fats. They accumulate with age and can impair tissue function by stiffening structural proteins and promoting inflammation. In this study, one of the first to measure AGEs in this context, skin AGE score fell from 3.1 to 2.7.

“For years, people with diabetes have been told to count calories and measure portions,” said Hana Kahleova, MD, PhD, the lead author of the study and director of clinical research at the Physicians Committee for Responsible Medicine. “This study shows that a simple shift in what you eat – toward vegetables, whole grains, legumes, and fruit – can reduce the fat clogging the liver by a third and improve how the pancreas makes insulin, without anyone having to count a single calorie.”

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 ethical journalism and sustains our future.

Literature

[1] Kahleova, H., Petersen, K., Shulman, G. I., Znayenko-Miller, T., Dufour, S., Brennan, H., … & Barnard, N. D. (2026). Changes in ectopic lipids, insulin sensitivity, and beta cell function after a low-fat vegan diet in adults with type 2 diabetes: a 16-week single-arm clinical trial. BMJ Open Diabetes Research & Care, 14(5).

[2] Chang-Chen, K. J., Mullur, R., & Bernal-Mizrachi, E. (2008). β-cell failure as a complication of diabetes. Reviews in Endocrine and Metabolic Disorders, 9(4), 329-343.

[3] Semba, R. D., Nicklett, E. J., & Ferrucci, L. (2010). Does accumulation of advanced glycation end products contribute to the aging phenotype?. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 65(9), 963-975.

Inflamed lower back discs

An Anti-Senescence Gene May Fight Spinal Disc Deterioration

In Aging Cell, a team of researchers has described how a little-known gene, ZNF865, has a significant influence on back pain through the regulation of cellular senescence.

Lower back pain and senescence are related

The link between cellular senescence and back pain has been thoroughly documented, particularly in the context of intervertebral disc degeneration (IVDD) [1], and in both rats and people, senescence accumulates as discs deteriorate [2]. These cells and their SASP contribute to the pain both directly and indirectly, as they both inflame the area and cause the extracellular matrix to deteriorate [3]. Targeting these cells through senolytics has shown some results in animal models; giving 14- to 23-month-old mice the senolytic combination of dasatinib and quercetin was found to significantly reduce their IVDD [4].

Using CRISPR technology, this team has previously investigated ZNF865 in the context of bioengineered intervertebral disc cells, finding that it increases cartilage, maturation, and overall performance [5]. Little other work has been done on ZNF865, although one previous paper has noted that people with an ineffective version of this gene have unique problems with neurological development and other organs [6]. As this team’s previous RNA sequencing work has also linked ZNF865 to senescence [5], the researchers took another look, focusing on its effects in that context.

Little known but highly necessary

These researchers first performed another RNA sequencing analysis, using degenerative human nucleus pulposus cells (dhNPCs) along with cells derived from fat tissue and the well-known human embryonic kidney cell line HEK293. In all three cell types, ZNF865 was found to be related to cellular replication, DNA repair, mTOR, and senescence.

In dhNPCs, ZNF865 is substantially lower than in healthy human nucleus pulposus cells (hNPCs). However, in hNPCs, ZNF865 decreases with age. This was measured with samples taken from lower back pain patients and trauma patients. In mice, this was confirmed with analyses at 4, 12, and 24 months of naturally aged wild-type animals. Unsurprisingly, dhNPCs were found to have significantly more markers of DNA damage than hNPCs.

The researchers then used CRISPR technology to silence the ZNF865 gene in hNPCs. Compared to an unsilenced control group, the affected cells had roughly five times the markers of cellular senescence along with a significant increase in markers of DNA damage.

The opposite experiment was then performed: using CRISPR to boost ZNF865 in dhNPCs. The treated cells had more rapid cellular proliferation and had their markers of cellular senescence reduced nearly to those of hNPCs, including those of SASP expression and inflammation. DNA damage was also significantly reduced, and the treatment group expressed more collagen as well, suggesting benefits for the extracellular matrix.

Promising cellular and rat data

A chromatin accessibility analysis confirmed these benefits. Administering ZNF865 to dhNPCs restored their chromatin accessibility to be much more like that of hNPCs, reducing the number of differences in this area by 94% and giving them no upregulated pathways compared to hNPCs. RNA expression analysis bolstered these findings, showing that ZNF865 upregulation had given these cells a healthier overall gene expression phenotype.

The researchers then confirmed the effects of ZNF865 in living animals. Silencing its ortholog in rat NP cells using a CRISPR vector and injecting those cells directly into the rats’ vertebral discs, the team found that the animals developed signs of degenerative disc disease in less than two months, including increased pain sensitivity, along with increases in cellular senescence, SASP proteins, and genetic damage.

While these results are informative, they are limited to cells derived from a limited number of people and an experiment that demonstrated the results of depriving it from rats. The researchers note that the molecular mechanisms of ZNF865’s effectiveness are undetermined, and they lament that there are no treatments other than CRISPR that are known to directly affect ZNF865 in cells; there are no antibodies, inhibitors, or activators yet developed for it. For this research to be made into a therapy suitable for human use, a workable approach will first have to be developed and given to an animal model to demonstrate that ZNF865 can mitigate IVDD or another senescence-related disease in vivo.

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 ethical journalism and sustains our future.

Literature

[1] Wang, F., Cai, F., Shi, R., Wang, X. H., & Wu, X. T. (2016). Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthritis and cartilage, 24(3), 398-408.

[2] Gruber, H. E., Ingram, J. A., Norton, H. J., & Hanley Jr, E. N. (2007). Senescence in cells of the aging and degenerating intervertebral disc: Immunolocalization of senescence-associated β-galactosidase in human and sand rat discs. Spine, 32(3), 321-327.

[3] Zhang, G. Z., Liu, M. Q., Chen, H. W., Wu, Z. L., Gao, Y. C., Ma, Z. J., … & Kang, X. W. (2021). NF‐κB signalling pathways in nucleus pulposus cell function and intervertebral disc degeneration. Cell proliferation, 54(7), e13057.

[4] Novais, E. J., Tran, V. A., Johnston, S. N., Darris, K. R., Roupas, A. J., Sessions, G. A., … & Risbud, M. V. (2021). Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nature communications, 12(1), 5213.

[5] Levis, H., Lewis, C., Fainor, M., Lawal, A., Stockham, E., Weston, J., … & Bowles, R. D. (2025). Targeted CRISPR regulation of ZNF865 enhances stem cell cartilage deposition, tissue maturation rates, and mechanical properties in engineered intervertebral discs. Acta biomaterialia, 191, 276-291.

[6] Bradbrook, S. M., Graham, G., Carter, M. T., Kibaek, M., Fagerberg, C., Larsen, M. J., … & Marcadier, J. (2026). De novo truncating variants in ZNF865 cause a novel neurodevelopmental disorder. American Journal of Medical Genetics Part A, 200(1), 244-252.

Gut bacteria

Gut Bacteria Molecule Slows Atherosclerosis in Mice

A new study highlights a fatty acid produced by a particular genus of bacteria as a “natural statin,” suggesting a new way of treating atherosclerosis [1].

Bacteria and cholesterol

Atherosclerosis develops when cholesterol-rich particles accumulate in arterial walls, driving inflammation and plaque buildup. The liver helps mitigate this process by removing low-density lipoprotein (LDL), which is known for its negative effects, from the bloodstream through LDL receptors that capture those particles and deposit them in cells.

Gut bacteria are known to be able to influence cholesterol metabolism through the molecules they produce [2]. Previous research has found that several species of the genus Bacteroides are less abundant in people with atherosclerotic cardiovascular disease. A group of Chinese researchers decided to dig deeper into this phenomenon and published their results in Nature.

First, the researchers analyzed gut microbial sequencing data from people with atherosclerotic cardiovascular disease as well as healthy controls. B. uniformis stood out as the most abundant bacterial species associated with the healthy group.

They then administered the bacterium to male mice lacking Apoe, a gene involved in clearing cholesterol-rich particles. These mice quickly develop atherosclerosis when on a high-fat diet. Atorvastatin, an established cholesterol-lowering drug, was used as positive control.

Twelve weeks of B. uniformis treatment reduced plaque area in the aorta and aortic root. It also lowered the overall plaque burden, circulating LDL cholesterol, total cholesterol, and triglycerides. HDL cholesterol did not change significantly.

Importantly, this is compared to vehicle-fed controls by the end of the experiment, rather than to baseline, which was not measured. Hence, the experiment demonstrated slowing, but not necessarily reversing, atherosclerosis. Atorvastatin produced comparable or slightly better results.

The treatment also reduced the number of plaque-associated macrophages, the immune cells that take up lipids and contribute to plaque development, and shifted the local immune environment toward a less inflammatory profile.

Dampening cholesterol production

The researchers also examined gene and protein activity in the liver. B. uniformis increased expression of LDL receptors and activated SREBP2, a regulatory protein that responds to low cellular cholesterol.

To test whether increased LDL uptake actually mattered, the researchers disabled the LDL receptor gene selectively in the liver. Without these receptors, the bacterium lost its ability to improve blood lipids, plaque burden, or inflammation, showing that working liver LDL receptors are necessary for the protective effect.

But why was this low-cholesterol response activated? The researchers found that B. uniformis actually reduced cholesterol synthesis in the liver. They hypothesized that decreased cholesterol production in liver cells prompts them to upregulate LDL receptors and draw more cholesterol out of the bloodstream, causing blood LDL levels to drop.

Next, the researchers asked whether the effect required living bacteria or could be reproduced by something they released. Dead bacteria did not do the trick, but an extract of the bacteria’s culture fluid did. Together, these results implicated a molecule produced by metabolically active bacteria.

The molecule in question was identified as pentadecanoic acid – a saturated fatty acid with 15 carbon atoms (“odd-chain”), also known as C15:0. It activated the same SREBP2-LDL receptor pathway.

Same pathway, smaller effect than atorvastatin

The researchers then gave purified C15:0 to atherosclerosis-prone mice for eight weeks, again with atorvastatin as a positive control, both at 25 mg/kg three times weekly. C15:0 reduced plaque burden by about 50% and lowered total and LDL cholesterol. It also reduced macrophage accumulation in plaques and systemic inflammatory markers. Atorvastatin, however, performed noticeably better.

Atorvastatin comparison

Like the bacterium, C15:0 reduced cellular and liver cholesterol. The researchers then investigated HMG-CoA reductase, an enzyme controlling a key step in cholesterol synthesis and the target of statin drugs. The experiments showed that C15:0 directly bound the enzyme and inhibited its activity.

However, C15:0 is a weaker inhibitor than atorvastatin, consistent with its more modest effect on atherosclerosis. The authors suggest that its greater persistence and exposure in mice might partly compensate for this.

Finally, the researchers measured C15:0 in people with abnormally high blood lipid levels (dyslipidemia) and healthy controls. The former had significantly lower C15:0 concentrations. Reanalysis of existing microbial sequencing datasets also showed lower levels of C15:0-production genes in people with atherosclerotic cardiovascular disease.

The findings underline new ways in which the microbiome might be harnessed to protect the heart, said study co-author Wenjing Zhao, a microbiologist at Sun Yat-sen University in Shenzhen, to Nature. However, more studies – especially in humans – are needed. Currently, it is not clear that C15:0, which can be purchased as a supplement, is superior to statins in any way. However, this still might prove to be the case; for instance, if further research shows a better safety profile or a larger tolerable dose.

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 ethical journalism and sustains our future.

Literature

[1] Yin, C., Chen, Y., Lin, G. et al. (2026). A gut microbial odd-chain fatty acid alleviates atherosclerosis in mice. Nature.

[2] Haghikia, A., Zimmermann, F., Schumann, P., Jasina, A., Roessler, J., Schmidt, D., … & Landmesser, U. (2022). Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism. European heart journal, 43(6), 518-533.

[3] Jie, Z., Xia, H., Zhong, S. L., Feng, Q., Li, S., Liang, S., … & Kristiansen, K. (2017). The gut microbiome in atherosclerotic cardiovascular disease. Nature communications, 8(1), 845.

Proteins or extracellular vesicles

Untangling Differences in Senescent Cellular Signaling

In Aging, researchers have described the differences between the secretions of cells driven senescent through a cancer gene and cells that stopped proliferating due to p16 expression.

A difference of kind

The SASP is a mix of many components that have various effects on the cells exposed to it. While inflammatory factors, such as cytokines and matrix metalloproteinases, are the most well-known of these, it also consists of ions, various metabolites, and exosomes: encapsulated cellular contents that cells use to signal one another. While exosomes have been researched for their therapeutic value [1], and we have reported on beneficial exosomes’ life-extending effects, exosomes secreted by senescent cells do the opposite [2].

This paper focuses on cells exhibiting the biomarker p16, which is encoded by the gene CDKN2A. This particular biomarker has been heavily linked to senescence, and purging p16-expressing cells from mice lengthens their lives [3]. However, Judith Campisi’s lab had noted that cells that were induced into senescence through p16 express different SASP components [4].

A SASP without inflammation

These researchers took a closer look at such differences, using IMR-90 fibroblasts to directly compare the secretions of ordinary senescent cells to those of p16-expressing cells and non-senescent cells. The first group was driven senescent through the oncogene H-RASG12V (RAS), while the second was made to express p16 through a specific viral vector.

As expected, the secretions of all three groups was substantially different. The RAS group secreted the inflammatory SASP component IL-1β, while the other two did not secrete it at all. While mRNA analysis found that the p16 group was producing IL-6, it secreted even less of it into its environment than the control group did. However, while the control group did not secrete any small extracellular vesicles (sEVs), the RAS group secreted many, and the p16 group secreted slightly more.

Cells spread their own type of senescence

These sEVs caused recipient non-senescent cells to behave much like the cells that secreted them. sEVs from p16 cells induced p16 expression in their recipients, yet they did not encourage the recipients to secrete inflammatory factors such as IL-6 and IL-8. sEVs from RAS cells were inconsistent in encouraging p16 expression, but they did encourage the production of these inflammatory cytokines. sEVs from both types stimulated DNA damage as measured by the biomarker γH2AX.

The researchers confirmed their findings by exposing babies’ fibroblasts in vitro to sEVs derived from the fibroblasts of older people. Even without the rest of the SASP, these older EVs were fully capable of driving the young cells into senescence, as measured by the biomarker SA-β-gal.

This paper holds that the SASP is fundamentally divided into two different portions: a soluble fraction (the sSASP), which consists of proteins and other relatively simple components, and a fraction that consists of extracellular vesicles (the evSASP). While the p16-expressing cells used in this experiment did not secrete the sSASP, they secreted the evSASP, which was found to have negative effects even without classical inflammatory factors.

This is exploratory cellular research, and the specific contents of the sEVs were not discovered, nor was any RNA transcription done in the recipient cells. The researchers suggest that their cargo may be genotoxic in nature and activates stress responses in the recipient cells. Whether or not it is feasible to target sEVs or their originating machinery is not yet clear.

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 ethical journalism and sustains our future.

Literature

[1] Ripoll, L., Zickler, A. M., Vader, P., El Andaloussi, S., Verweij, F. J., & Van Niel, G. (2026). Biology and therapeutic potential of extracellular vesicle targeting and uptake. Nature Reviews Molecular Cell Biology, 27(5), 358-376.

[2] Takasugi, M., Okada, R., Takahashi, A., Virya Chen, D., Watanabe, S., & Hara, E. (2017). Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nature communications, 8(1), 15729.

[3] Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189.

[4] Coppé, J. P., Rodier, F., Patil, C. K., Freund, A., Desprez, P. Y., & Campisi, J. (2011). Tumor suppressor and aging biomarker p16INK4a induces cellular senescence without the associated inflammatory secretory phenotype. Journal of Biological Chemistry, 286(42), 36396-36403.

Forever Healthy Foundation

Evipedia Goes Hugging Face

With more than 860 evidence reviews on health and longevity interventions, Evipedia is now probably one of the deepest online sources in this area.

We have always been extremely open to sharing our data and making it accessible in any form that supports projects and tools that enable people to make better decisions about their health and longevity.

Now, we are taking it to the next level by making all our reviews available on HuggingFace. Our whole dataset, including all updates, published and refreshed daily.  One row per review with all metadata and full Markdown, ready to drop into any ML or RAG pipeline.

What’s in Evipedia

Evipedia is a comprehensive, continuously updated online encyclopedia that provides much-needed, accurate, and up-to-date information on a wide range of health and longevity-related interventions.

  • Free to Use Evipedia is completely free to use and open to everyone. We built Evipedia as a backbone tool for the whole longevity and rejuvenation community. Our goal is to empower individuals with knowledge to make informed decisions about their health and longevity.
  • 870+ Evidence Reviews Including whole-body therapies, brain health, skin rejuvenation, hormone optimization, peptides, psychedelics, medications, blood and plasma therapies, complementary cancer approaches, foundational habits, diets, foods, probiotics, botanicals, isolates, and many more.
  • A Dual Structure for Every Entry Each intervention has a one-page Quick Reference Sheet for an at-a-glance protocol, benefits, risks, contraindications, and monitoring, plus a Full Evidence Review for in-depth analysis.
  • Continuous Updates Entries are continuously updated to reflect the latest developments in health and longevity. On average, reviews are refreshed every 4-6 weeks, ensuring access to the most current information available.
  • Full Audit and Quality Transparency Every “Quick Reference Sheet” and “Evidence Review” on Evipedia includes an Audit Report that outlines the detailed audit criteria and the history of audits and fixes applied to the documents.
  • Stable Permalinks – Beautiful Sharing Cards Every intervention has a fixed, short URL and a purpose-designed social sharing card — ideal for citing a compound in a supplement stack or anchoring a claim in an online discussion.
  • AI & Agent-friendly, Extensive Integration Support Built as a backbone service for the longevity and rejuvenation community, Evipedia features a wide variety of AI integration tools and an easily accessible API. All are free to use, under an AI- and agent-friendly site policy and the Creative Commons 4.0 license.
  • Built on AI4L Evipedia is built on top of our open-source AI4L framework, which enables anyone to create high-quality, evidence-based reviews of health and longevity interventions. At the core of AI4L is our novel “Audit-Driven Prompting” approach to generate hallucination-free, accurate, and well-structured reviews using frontier AI models.

About Forever Healthy

Forever Healthy Foundation is a private, humanitarian initiative with the mission of enabling people to vastly extend their healthy lifespan. More at forever-healthy.org

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 ethical journalism and sustains our future.
Cell and organelles

Declining Autophagy Impairs Senescent Cell Clearance

A new study links an age-related decline in cellular maintenance to impaired immune clearance. Activating the pathway reduced signs of senescence in aged mice [1].

Senescence and autophagy

Cellular senescence, which occurs when cells stop dividing and start emitting largely pro-inflammatory stress signals, the senescence-associated secretory phenotype (SASP), is a double-edged sword. On the one hand, it plays an important role in processes like development and wound healing as well as in regeneration in some animals. On the other hand, with age, senescent cells accumulate in tissues, driving inflammation, fibrosis, and cancer, which earned cellular senescence a place on the Hallmarks of Aging list.

One of the reasons for the age-related accumulation of senescent cells might be the declining ability of immune cells to clear them away. A new study from the Albert Einstein College of Medicine, published in Nature Aging, investigates a mechanism that might be responsible for that.

The researchers focused on chaperone-mediated autophagy (CMA). Autophagy is the process of degrading and removing intracellular junk, such as misfolded proteins, and CMA is a distinct pathway mediated by the chaperone protein HSC70, which recognizes suitable proteins and delivers them to a receptor called LAMP2A. The proteins then unfold and pass into the cell’s lysosomes for degradation. This process differs from macroautophagy, the pathway that delivers cellular material to lysosomes in tiny vesicles.

Previous research showed that CMA generally declines with age [2] and rises when cells enter senescence [3], suggesting that it mediates this transition. The researchers asked whether this failure to increase CMA alters the course of senescence onset and whether CMA decline also compromises immune clearance.

CMA mediates senescence and macrophage function

The researchers isolated ear fibroblasts from 4-month-old (young) and 23-month-old (old) mice. The old fibroblasts were not initially more senescent according to the markers used. Both young and old cells could be induced into senescence with the drug palbociclib, but young fibroblasts increased CMA after senescence induction, while old fibroblasts started with lower activity levels and failed to increase them.

The team then reduced LAMP2A in mouse fibroblasts to ask whether CMA loss itself causes senescence. CMA-deficient cells acquired some senescence-like features but remained proliferative until given a senescence-inducing treatment. After palbociclib treatment, both normal and CMA-deficient cells stopped proliferating, but their overall marker profiles differed. This suggests that while CMA deficiency could not cause growth arrest by itself, it changed the resulting senescent phenotype.

Disabling CMA in young cells reproduced many of the changes found in old cells, both before and after senescence induction. Normally, cells entering senescence remove certain proteins and reorganize their metabolism. Both old and CMA-deficient cells partially failed in that reorganization. This suggests that CMA decline contributes to the aging-associated altered senescent state.

Once induced into senescence, CMA-deficient cells developed a distinct secretory profile. The researchers investigated its effect by applying a medium conditioned by these cells onto normal fibroblasts for five days. Secretions from CMA-deficient cells induced senescence-associated changes in neighboring normal cells, even when the donor cells had not themselves been turned senescent.

The researchers then wanted to see whether these altered secretions suppress CMA and cell-clearing activity in macrophages, immune cells that help remove unwanted cells. Macrophages from old mice already had lower CMA activity than those from young mice. Moreover, the medium conditioned from senescent fibroblasts suppressed CMA in young macrophages. Secretions from CMA-deficient fibroblasts – even non-senescent – were particularly inhibitory.

The researchers then co-cultured senescent fibroblasts with either normal or CMA-deficient macrophages. When the macrophages lacked CMA, they were able to clear fewer fibroblasts, regardless of whether the fibroblasts themselves had functional CMA. This suggests that CMA-deficient cells secrete molecules that compromise CMA and function in the immune cells needed to clear them. The researchers then confirmed this decline in macrophage cell-removing abilities with a series of experiments.

Increasing CMA slows lung fibrosis

The researchers next examined mice in which LAMP2A was selectively deleted in macrophages and some other immune cells. Late in life, these mice showed an increased senescence burden across several tissues, although this varied by sex and measurement.

Since senescent cells participate in wound clearing, the researchers created skin wounds in these mice. Mice with CMA-deficient immune cells healed more slowly and retained more senescent cells at the wound site. The team confirmed that the problem was decreased macrophage function rather than recruitment to the wound site.

What would happen if CMA were increased rather than suppressed in old mice? The researchers administered CA77.1, a drug known to activate CMA, to aged mice and found that these generally had lower senescence-associated measurements than untreated aged mice, with several results moving toward young-control levels. However, the effects differed across tissues, sexes, and markers.

The researchers then investigated idiopathic pulmonary fibrosis (IPF), a lung-scarring disease associated with senescence. Lysosomes isolated from human fibrotic lungs had reduced LAMP2 protein levels and impaired uptake of a CMA substrate.

Finally, the team induced lung fibrosis in mice. CA77.1 treatment started soon after injury (day 2), but not on day 7, preserved body weight and substantially reduced subsequent lung fibrosis, suggesting that early CMA activation limits disease progression.

“In older animals, age-related changes in both senescent cells and the immune cells responsible for removing them allow these zombie cells to accumulate and play a role in disease,” said study leader Ana Maria Cuervo, M.D., Ph.D., co-director of the Institute for Geroscience at Einstein. “By restoring cellular recycling, we may be able to help the body’s own defenses clear these cells more effectively. The next challenge is determining whether this approach can eventually be developed into a safe treatment for age-related diseases in people.”

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 ethical journalism and sustains our future.

Literature

[1] Sereda, R., Lindenau, K., Diaz, A. et al. (2026). Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells. Nature Aging.

[2] Khawaja, R. R., Martín-Segura, A., Santiago-Fernández, O., Sereda, R., Lindenau, K., Mccabe, M., … & Cuervo, A. M. (2025). Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging. Nature Aging, 5(4), 691-708.

[3] Rovira, M., Sereda, R., Pladevall‐Morera, D., Ramponi, V., Marin, I., Maus, M., … & Serrano, M. (2022). The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging cell, 21(10), e13707.

Brain and walking

The Biomarkers That Predict Mortality Risk

Researchers have discovered key biomarkers that are strongly linked to all-cause mortality and identified four measurements with independent predictive power.

Biological versus chronological

This paper opens with a discussion of a familiar fact for people interested in living longer: one’s biological age is not the same as one’s chronological age [1]. Biological age gives a more accurate indication of a person’s current and future health [2]. The authors touch upon the benefits and drawbacks of several well-known biomarkers; grip strength and gait speed are reliable [3] but, as these authors note, only begin to decline much later in life; neurological imaging is similarly reliable [4] but is expensive to perform and, like physical function tests, does not directly capture molecular changes. Telomere attrition, once a key focus of aging research, may not be as useful as previously hoped [5].

Epigenetic clocks and proteomic biomarkers have been developed to more accurately gauge aging and mortality risk. This includes the well-known GrimAge epigenetic mortality clock and its second version [6], which is referenced in this study. Organ-specific proteomics have been found to be strongly related to aging and disease as well [7].

This paper directly pits these various biomarkers against each other, gauging how valuable they are for predicting mortality and how much they overlap. The data source is LBC1936, a cohort of 861 people who were born in 1936, participated in a mental examination at age 11, and had their proteomic, physical, and neurological biomarkers examined every three years between the ages of 70 and 89.

GrimAge2 comes out on top

The researchers first examined this cohort’s organ age gaps: the difference between the chronological and biological age of each major organ. Consistent with previous research [7], these differences were only loosely correlated in the same individual. Even people with an extreme age gap in one organ were unlikely to similarly age in other organs.

Unsurprisingly, of all the various biomarkers that the researchers used, GrimAge2 was found to be the most closely connected with all-cause mortality. Organ age gaps were also highly associated with all-cause mortality, most notably in the liver, immune system, heart, pancreas, and brain.

However, some metrics of physical function were more closely related to mortality than any organ-specific clock. These included total brain volume and grey matter volume, overall cognitive function (g), and forced expiratory ratio and forced vital capacity, two metrics of lung function. Telomere attrition in leukocytes, on the other hand, was found to have no significant relationship.

The researchers then used statistical methods to examine how closely these biomarkers overlap with one another. As a composite biomarker, GrimAge2 was strongly related to all of the organ-specific proteomic markers along with many of the other markers. Walking time, a biomarker with similar predictive power as immune and heart proteomics, was strongly correlated with other biomarkers. While organ age gaps were loosely correlated with each other, they were uncorrelated with physical biomarkers as a whole.

The researchers then sought the biomarkers with the most independent predictive power when excluding other biomarkers, aiming to minimize redundancy. Four stood out in this regard: white matter volume, total brain volume, walking time, and the cognitive metric g. Combining these four markers accounted for 19% of the variance in mortality risk, and including the other 17 only raised this by 4%.

One protein stands out among many

Finally, this study took a look at proteins themselves. GDF15, which has been associated with cellular senescence, was found to be the protein most closely related to mortality risk after adjustment for lifestyle factors, and, of all the biomarkers in this study, it was only surpassed by GrimAge2 in overall predictive power. The neuropeptide NPS was found to have the strongest negative association: people who express more NPS are less likely to die of any cause.

As expected, the proteins most associated with mortality were associated with inflammation, including chemokine and interleukin signaling. The proteins that were associated with longer lifespans, on the other hand, were related to the maintenance of genomic stability, such as retroelement regulation and chromatin management.

The researchers acknowledge this study’s limitations, including the fact that this relatively small cohort only includes healthy Scottish people. This study also used time-point measurements and did not consider trajectories. This was also solely an observational study and did not delve into mechanisms. However, its core finding, that brain imaging and lung measurements are more effective than organ-specific proteomic clocks in predicting overall mortality, offers sobering insight.

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 ethical journalism and sustains our future.

Literature

[1] Salih, A., Nichols, T., Szabo, L., Petersen, S. E., & Raisi-Estabragh, Z. (2023). Conceptual overview of biological age estimation. Aging and disease, 14(3), 583.

[2] Jylhävä, J., Pedersen, N. L., & Hägg, S. (2017). Biological age predictors. EBioMedicine, 21, 29-36.

[3] de Souza, A. F., de Oliveira, D. C., Ramírez, P. C., de Oliveira Máximo, R., Luiz, M. M., Delinocente, M. L. B., … & da Silva Alexandre, T. (2025). Low gait speed is better than frailty and sarcopenia at identifying the risk of disability in older adults. Age and Ageing, 54(4), afaf104.

[4] Fletcher, E., Gavett, B., Harvey, D., Farias, S. T., Olichney, J., Beckett, L., … & Mungas, D. (2018). Brain volume change and cognitive trajectories in aging. Neuropsychology, 32(4), 436.

[5] Wang, Q., Zhan, Y., Pedersen, N. L., Fang, F., & Hägg, S. (2018). Telomere length and all-cause mortality: a meta-analysis. Ageing research reviews, 48, 11-20.

[6] Lu, A. T., Binder, A. M., Zhang, J., Yan, Q., Reiner, A. P., Cox, S. R., … & Horvath, S. (2022). DNA methylation GrimAge version 2. Aging (Albany NY), 14(23), 9484.

[7] Oh, H. S. H., Rutledge, J., Nachun, D., Pálovics, R., Abiose, O., Moran-Losada, P., … & Wyss-Coray, T. (2023). Organ aging signatures in the plasma proteome track health and disease. Nature, 624(7990), 164-172.

FDA at ARDD

FDA Leaders Name Longevity a Priority at ARDD

At a panel in Boston, senior officials announced plans to include aging in the agency’s regulatory science agenda and discussed how therapies could move toward approval.

Longevity has a partner

The 2026 edition of the Aging Research and Drug Discovery Meeting (ARDD) kicked off yesterday. This is one of the biggest and longest-running longevity conferences, and it has been traditionally held in Copenhagen. This year, it arrived in Boston instead, with a slightly truncated schedule (three days versus the usual five) but with an equally impressive lineup and program.

Day 1 was all about longevity going mainstream, with discussions centered on policy, regulation, and clinical translation. Gone are the days when longevity events were largely ignored by the people calling the shots. This time, a panel titled “Matching Clinical Trials of Therapeutics & Regulatory Mandates” boasted four FDA heavyweights. Prompted by moderator Andrew Brack, Program Manager at ARPA-H, they described the agency’s growing interest in aging and longevity and discussed how gerotherapeutics could progress toward approval.

“This is an important topic for the agency and HHS at large,” said Lowell Zeta, Deputy Commissioner for Strategic Initiatives. “It’s a defining moment, an inflection point for the future of FDA and how we adapt to the rapidly evolving science in this space.”

The most tangible announcement was that aging and longevity will feature in the forthcoming update to FDA’s Focus Areas of Regulatory Science (FARS). Drawing applause from the crowd, Steven Kozlowski, the agency’s Chief Scientist, described FARS as “high-level principles on areas that are very, very important to us; aging and longevity will be one of those topics.” Kozlowski gave a tentative release target of the 2027 fiscal year, which also began yesterday. The document’s previous version was released several years ago.

Seeking approval

Beyond that announcement, the panelists drilled down into what an approval process for longevity therapies could look like. Jeffrey Siegel, Director of the Office of Drug Evaluation Sciences, outlined two possible approaches to demonstrating broader effects on aging. One would involve accumulating evidence that a treatment benefits several age-related conditions; another, drawing on the concept of intrinsic capacity, would measure deterioration across multiple physical and mental capacities in a defined population and show that treatment slows it.

Justin Penzenstadler, Acting Associate Director of the Office of Cardiology, Hematology, Endocrinology, and Nephrology, expects early trials that could support approval to focus on age-related comorbidities or mortality. Collecting functional assessments alongside those outcomes could help establish additional metrics for later trials.

One obvious caveat is that a broader aging claim needs evidence beyond a drug’s established benefits. If a cardiometabolic treatment extends survival through its known cardiovascular effects, that alone does not demonstrate broader geroprotective activity, Penzenstadler noted.

Safety also shapes the choice of trial population. Decades of treatment, potentially modest benefits, and relatively low baseline risk make for a demanding benefit–risk calculation. As Penzenstadler put it, “We’re thinking about potentially treating somebody for thirty years to derive a couple-year benefit.” Consequently, he favors initial trials in older, higher-risk populations, where the calculation “is a bit more straightforward.”

Biomarkers could help shorten trials by serving as proxies for clinical outcomes – but only with evidence that they reliably reflect benefit. The panel discussed collecting both clinical outcomes and candidate biomarkers in trials to build that evidence.

Siegel distinguished prognostic biomarkers, which predict future risk, from surrogate endpoints. “A surrogate endpoint biomarker may also be prognostic, but it has the additional feature that it changes with treatment, and that change reflects the clinical benefit downstream,” he said.

Collaboration and convergence

Asked how the longevity community could advance regulatory progress, Penzenstadler’s main recommendation was to establish a pre-competitive consortium to work out “a cookbook of biomarkers” to include in trials. Agreeing on compatible trial designs up front would allow different companies to pool their results and build evidence for biomarker validation. “I think that’s probably the number one thing that is actionable that will push the field,” he said.

His second recommendation was to hold regular, structured meetings between regulators, researchers, and industry, helping both sides understand emerging evidence and the challenges of developing therapies.

Several recommendations voiced during the panel echoed initiatives that are already underway. For instance, the proposed Targeting Aging with Metformin (TAME) trial would examine multiple age-related diseases, while XPRIZE Healthspan focuses on muscle, cognitive, and immune function. These correspond to the two approaches described by Siegel. Likewise, the Biomarkers of Aging Consortium reflects the field’s recognition that developing better measurements requires collaboration.

This convergence comes amid growing engagement between FDA officials and the longevity field, which seems to have intensified further this year. FDA participation in events such as A4LI’s June DC summit provided ample opportunities for cross-pollination. What we heard at ARDD suggests that this dialogue may be beginning to bear fruit.

The panel also gave longevity sponsors a concrete address: Penzenstadler identified his clinical review office as being responsible for aging as an indication. He encouraged sponsors to submit actual protocols and supporting evidence through the Investigational New Drug (IND) process, giving FDA something specific to assess and respond to.

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 ethical journalism and sustains our future.