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A new UNC initiative aims to bring AI tools to rural and low-resource health care clinics
From transcription tools to customer service, many small clinics don't have the bandwidth to navigate AI.
Cleveland Clinic Partners with Luminai to Transform Health System Operations
Collaboration applies AI automation to complex administrative processes at enterprise scale – with fax referral transcription as the first use case
Smart ring reads your sweat to measure glucose, ketones, and more
Smart rings are everywhere: smart rings that can record your verbal notes and send them to your cellular telephone for transcription, smart rings that let users pose questions to AI and get answers via earbuds, and smart rings that help athletes reach their peak performance.
Google’s new AI transcription edits out your ‘ums’ and ‘ahs’
It also removes “ums” and other filler words for you.
Pixel 11’s Gboard Rambler is prompt-based, rather than real-time
Gboard Rambler is likely the flagship Gemini Intelligence feature on the Pixel 11 series, but it’s not the real-time transcription...
Gemini for macOS rolling out voice control and Gboard Rambler-level transcription
After previewing at I/O 2026 in May, Gemini for macOS is now rolling out advanced voice control capabilities.
The AI Backlash Companies Can’t Ignore | AI & Business for July 21
Plus, China’s latest AI advances, always-on transcription and the perils of big AI contracts.
Transcription by Ben Lerner wins Orwell prize for political fiction
Judging chair calls Lerner’s novel a ‘funny, brainy and timely’ study of our appetite for technology, while Karen Bartlett wins the nonfiction prize for The Escape from Kabul
The cult of objectivity has broken consciousness science
With 22 competing theories and no consensus in sight, the science of consciousness is lost. In this exclusive IAI interview, Berkeley psychedelics researcher and bestselling author of a new book on consciousness Michael Pollan insists that even though consciousness lies beyond traditional forms of scientific investigation, we should resist becoming dualists who see it as something radically different from ordinary stuff in the world. Instead, he makes the case for reimagining science itself: it must stop reaching for objective descriptions of physical reality, and instead embrace subjectivity as the indispensable core of all inquiry. Alasdair Craig: How did your experiences with psychedelics get you interested in consciousness?Michael Pollan: One of the things that happens on psychedelics is that they foreground consciousness. What formerly seemed perfectly transparent and ever present—and yet, non-existent, as water is to fish—suddenly you see it. The metaphor I use in the book is that psychedelics sponge the windscreen. Suddenly you realize: wow, there’s a windscreen, there is this phenomenon that’s mediating my relationship to reality. This is not an unusual realization on psychedelics. I think a lot of people are called to think about consciousness after psychedelic experiences. So that was the proximate inspiration for A World Appears: A Journey Into Consciousness (2026).And then there was a more specific way in which psychedelics influence the book. That was a particular experience I had on psilocybin. I had the sensation that the plants in my garden were conscious and returning my gaze, with their own point of view and agency, and I got curious as to how to evaluate an insight like that. I mean, what’s the truth quotient of insights you have on psychedelics? And I was reading William James—who, of course, wrote beautifully about mystical experience—and he said, we can’t judge the metaphysics here, but we should pay attention to two criteria: (1) How useful is it to think this is true? He was a pragmatist, of course. And (2) can we subject it to other ways of knowing to validate it? Because maybe we should treat these insights as hypotheses. And that’s kind of how I approach psychedelics, as a great generator of hypotheses, but they need to be tested against other ways of knowing. And so that led me down this long path exploring the science of plant intelligence and plant sentience.AC: I love your phrase, “smudging the windowpane of conscious experience.” So do you now start to think, actually, even when I’m not on psychedelics, I’m just seeing a screen all the time, which is not reality, but rather is my conscious experience, behind which reality is hidden?MP: Well, you know, not when I’m brushing my teeth and making breakfast! But yes, in meditation, certainly. I mean, one of the things you realize is that my experience happens to be this way now, but it could be another way. And many things can affect it. My morning coffee changes the screen in various ways, sharpens certain things.___The only tool we have to understand consciousness is consciousness.___There’s this wonderful metaphor in Aldous Huxley’s book, The Doors of Perception, where he thinks we channel consciousness, and that what the brain does is edit it, and there’s a reducing valve. And psychedelics open the reducing valve wider. I don’t know that I’m ready to buy into the idea that consciousness exists outside brains, but I do love that metaphor because there are times when you are more conscious than others. I know I’ve switched from window pane to valve, but you know, a camera aperture can open wider or narrower. And I do have a sense of that. I have a sense of when I’m being less conscious, and when I’m being more conscious, by which I mean, you know, more present, taking in more sensory information. So when you start thinking about consciousness as a matter of degree, that changes things also.I think when we scroll on social media, obviously, we’re conscious. But minimally so, because we don’t have to generate our own thoughts. We’re basically taking these little hits from other people and thinking their thoughts.The process of writing this book made me kind of relativize everyday consciousness as just one type, which is exactly what William James said. Normal consciousness is one type, separated by the flimsiest of screens from the other types.AC: If we stick with the metaphor of the smudge on the window that you get when you take psychedelics, it seems like we’re saying that consciousness has become like an object that you’re looking at, right? You’re looking at the smudge and that just is consciousness. But sometimes we’ll talk about consciousness as a state that you’re in, rather than an object you can perceive. You’re either conscious or you’re not conscious. So it’s difficult to really know what sort of thing we’re talking about when we talk about consciousness, right?MP: Yeah. When you say that consciousness is an object, what’s the subject? Consciousness also? The only tool we have to understand consciousness is consciousness. So we’re in a closed loop and when we get a perspective on consciousness, we’re not achieving any distance from it. That’s one of the problems with studying consciousness. Science is predicated on an objective, God’s eye view of things, and you never get that. There’s no such thing. SUGGESTED VIEWING The brain filters consciousness With Àlex Gómez-Marín But, yeah, there is this sense, I think, that consciousness is something you can approach. Certainly, when you’re writing and trying to recreate a conscious experience, it’s a fiction, but you’re standing back from it, and looking at it. But there’s no real subject-object distinction.AC: That’s so interesting, because when philosophers start talking about consciousness, they often talk about what they call “qualia”, which is their word for the felt experience of, say, the color red. And I think that way of speaking often makes us think of the qualia as an object, which you can see out there: the redness of red. But, as you say, we also want to collapse the subject-object distinction when we talk about consciousness. So there’s something strange going on here…MP: Oh, yeah, there are many strange things going on! *AC: Let’s talk about the varieties of consciousness. Apart from perceptions, there are, pains, emotions, thoughts, and so on. What is it that holds all this diversity together so that they all count as instances of consciousness? What is it that they all have in common?MP: Yeah, that’s a really good question. I mean, there is sensory information, right? Which we perceive coming from the world outside ourselves. And then there’s internal information, which is what’s called interoception. And this is very important too. This is where feelings come from—what are sometimes called homeostatic feelings—that are intended to get the brain to keep us in these narrow ranges of temperature and glucose and so on. That’s a very important part of consciousness. And according to some researchers, who I think are probably right, this is where consciousness begins, with these very primal feelings, like hunger and thirst and warmth and itch, and things like that. And then there’s this third thing, which is our thinking about thinking.And what holds all this together is, I think, the sense of self. Consciousness generates a self: it is probably an organizing principle. All this stuff is happening to the self. It’s a construct, I think, but it is very useful. It can connect all these different streams of consciousness to a single being or a place, metaphorically speaking.* AC: The first half of your book is about the science of consciousness. Is consciousness just another thing, like black holes or the origin of life, which we don’t yet understand, but which we should have every hope that science will one day get to the bottom of, or is there something special about consciousness that makes this unlikely?MP: It depends how you define science. As we define science now, it’s going be very difficult. Science since Galileo has had a set of rules or assumptions, which is that the proper remit of science is to deal with the objective, quantifiable, third-person world. And the physical sciences have done amazing work under that set of limitations. Galileo—for tactical reasons, not for philosophical reasons—said science should not deal with the soul, which at the time was what consciousness was considered to be. So what is subjective, what is qualitative, what is first person, we’re going to leave to the church, he said. And this was a good agreement, and it probably kept many scientists from getting burned at the stake. But it leaves science in an awkward spot, now that it wants to venture into that territory of qualities, of first-person experience. And I don’t think it has the proper tools. I think it will have to add to its toolkit in some way, and find a way to bring in phenomenology, or lived experience and introspection, which science is usually dismissive of.The challenge—we alluded to it earlier—is that the only tool you have to study consciousness with is consciousness. And what I mean by that is, the whole scientific enterprise is a manifestation of consciousness. As much as scientists like to flatter themselves with this idea that they attain a godlike perspective on what they study, when it comes to consciousness, there’s no such thing. And it’s fine for all the things you can step outside of and study from that perspective. But two areas it won’t work are consciousness and cosmology.___It could be that we live in this anomaly of not believing nature is conscious. And maybe psychedelics are teaching us something we’ve forgotten.___With cosmology, too, you have to study the universe from inside the universe. It’s not that cosmologists haven’t made progress. We know a lot about the age of the universe and expansion and things like that. But we can’t penetrate what happened before the Big Bang. We just don’t have the tools because we can’t stand outside.The fact that there are 22 full-scale theories of consciousness tells you all you need to know: we’re kind of lost. And I was surprised to find that we are more lost than I thought we were when I started this. I thought that there’d be leading theories, or that we had experiments that we could conduct that would nail some of this down. And the fact is, we don’t.So, I don’t know if science can solve it. But, of course, we can change the rules of science. A really influential book for me was a book called The Blind Spot, by two physicists, Marcello Gleiser and Adam Frank, and a philosopher, Evan Thompson. It’s a reminder that science is a social practice. It’s organized in a certain way and it can be organized in a different way. But it has this huge blind spot at the center of it, which is its failure to recognize that it is a form of consciousness itself, and it doesn’t have a good way of taking account of lived experience.AC: On the one hand, I think you want to resist traditional dualism, which would say that consciousness is something magical, something supernatural, right? But on the other hand, you’re accepting that there is this division in reality between the stuff that you can investigate objectively and measure, and so on—the stuff that science has been good at finding out about—and consciousness, which, for some reason, you can’t objectively measure. Some would take this to suggest that the dualism is actually right. Is there a way of reconciling these two strands of your thinking?MP: To call it magical is full of value judgement. I mean, you could just say immaterial. The interesting thing is, I think, that intuitively we’re all dualists. And I don’t know whether that’s because we’re children of Descartes and other cultures are less dualist than we are. Or it may be because that’s how consciousness feels. It feels different than the body. It feels separate from the body. But I don’t think we should trust that intuition.AC: So let’s think about ways that science might be changed to get at consciousness. I suppose the starting point would be the way that you begin the second half of your book. You have this nice line from William James, where he says, “We now begin our study of the mind from within.” Could you give us some sense of the ways of studying the mind from within? What does this involve?MP: I don’t know what that science looks like. But one of the points I’m making is that it depends on the humanities. I found that I learned as much, if not more, about consciousness, from reading novels and poetry. There is a sense of the fullness and complexity of consciousness that you don’t get in any scientific account. I interviewed this stream-of-consciousness writer and I approached her as an expert on consciousness, and she is. So I think that dialogue is really important.I’m reading Ben Lerner’s new novel, Transcription. Just read the first page of this novel: it’s a man falling asleep on a train, going to conduct an interview, and there is the experience of being in the train, facing backwards, there’s the view outside, but there’s a reflection of himself through which he’s seeing outside. There’s the memory of dropping his kids off at school. All this is going on in one moment of consciousness. Scientists aren’t going anywhere near that. But I think it’s useful for them to think about. That’s where we’re trying to go: like, how does such a layered experience happen? You know, it also makes you wonder, could a computer ever do this? And it gives you some doubt.*AC: Before we get to computers, perhaps we could talk briefly about plants. How did you come to feel that they are sentient?MP: Well, it was a psychedelic experience, and it’s not unusual on psychedelics. In fact, there’ve been studies about how people become animists during psychedelic experience. Their belief in animism arises after a single psychedelic experience.You know, most scientists would say this is all a myth. But we have only 400 years of the age of enlightenment and science. Before that, we were animists, and if you go around the world, most indigenous cultures are still animists, and children are animists, by and large, until they go to school. So it could be that we live in this anomaly of not believing nature is conscious. And maybe psychedelics are teaching us something we’ve forgotten.As I said, I wanted to test this idea, and see whether there was conventional scientific evidence for it. And there’s fascinating work going on in a field that calls itself—in a rather cheeky way—plant neurobiology. These are people who fully realize there are no neurons in plants, but they’re trolling conventional botanists! And they’re doing experiments that are demonstrating that plants can learn and remember, which is kind of amazing: how do you store a memory without neurons? They’re finding plants that can solve problems, that can hear and see. In fact, they have 20 senses to our five or six. For example, a bean plant looking for something to twine, and given a pole within eight inches or so of it, knows where that pole is and will aim its spiraling reach at that pole. What is that about? Is it bouncing signals off of it?One of the spookiest things is the fact that the same anesthetics that put us out put plants out. You might think that plants are already out, but they’re not. They’re just slow. If you take a plant with a fast behavior, like a Venus flytrap, and give it an anesthetic, it will stop reacting. So you have to ask yourself, what is lost when the plant is anaesthetized? Some state of alertness, of awareness, of its environment, of reactivity. I’m not prepared to call that consciousness, but maybe it’s sentience—which is a simpler form of consciousness, and involves the ability to sense what’s going on in your environment and assess what’s good and bad for you and act appropriately. That may be a universal quality of life.AC: Let’s turn from plants to AI. You point out that LLMs are trained on the internet rather than direct interactions with reality. You put this really nicely when you say the internet is not the world so much as a shadow cast by the world. So LLMs are living in this kind of shadow world, or in Plato’s cave, as you put it. What’s the significance of this for AI consciousness and moral consideration? And, to recall the beginning of our conversation, if we’re stuck behind a veil or screen of consciousness, are we also stuck in a kind of shadow world?MP: I don’t think they’re the same shadow worlds because our world includes nature and other people. And even if it’s mediated in some ways... There is a reality out there, and we are in relation to it, through consciousness. There’s friction with it. What’s missing from the LLMs is that friction with the real world. There’s more to the world than human representation, which is what they’re dealing with. And that means that so far, AI is a cultural technology for combining thoughts we’ve already had. SUGGESTED VIEWING Cracking the code for thought With Roger Penrose, Sabrina Gonzalez Pasterski, Max Tegmark, Güneş Taylor Genuine creativity is more than collage. A lot of what AI does now is tantamount to collage, putting this with that and you know, that’s part of art, certainly. But there are also genuinely new ideas that come into the world that don’t come in through manipulating the representations we already have. So it remains to be seen whether AIs can be truly creative in that more radical sense.But my arguments against AI becoming conscious have to do with the fact that the idea of AI consciousness is based on this faulty metaphor that the brain is a computer. There are dimensions in which the brain is like a computer—it certainly does its share of computation. But computers have this sharp distinction between hardware and software, and brains don’t. In a brain, hardware and software are identical. Every memory is a physical change to the brain. Brains are not interchangeable in the way computers are. So this idea that you could take the consciousness out and somehow run it on another substrate, a silicon substrate, seems foolhardy.Anyway, it’s a more extended argument, and I may be wrong. And when we move to computers that aren’t based on silicon—neuromorphic computers and things like that—all bets may be off.AC: Regarding your point about LLMs being stuck in the world of our representations—the internet or whatever—and not being able to interact with reality, are these representations, the world of the internet, themselves part of reality? We’ve created the internet, but it’s still a real thing that exists. And so while the LLMs may be trapped within that part of reality, they’re nevertheless within reality and interacting with it and so on. So it’s not obvious that there’s a barrier there to them becoming conscious and being creative.MP: Yeah, I mean, if our consciousness is built out of human culture, which is what we’re talking about with all those representations. But I tend to think consciousness comes a bit more out of nature and friction with the natural world, but...AC: So there’s a fundamental divide between the natural world and human artefacts?MP: And we lose track of that, and especially people in this computer world. You know, the people who are creating these AI systems, my guess is they’ve been into video games since the age of three, and they didn’t go outside a lot. And their own contact with nature is somewhat limited. I could be wrong, it’d be a very interesting thing to ask, all the wizards of AI, whether they like to go fishing and hiking and do things like that. Or were they on computers from a very early age? I interviewed Blake Lemoine, the Google engineer who came to believe that LaMDA, the Google LLM out at the time, was conscious and deserved personhood. It was very clear that he didn’t see a distinction between this bubble in which he lived and the real world. And I think we’ve all been distanced from the natural world, and this is taking us even further away. But it’s still there, you know, and we still have bodies, and we’re still mortal, and we don’t live in a simulation.AC: I think that’s a great place to finish. Michael Pollan, thank you very much!
Time matters: circadian genetics and the molecular logic of human health and disease
Nature Reviews Genetics - The circadian clock controls transcriptional and signalling networks across tissues to maintain homeostasis, with pathological consequences to its disruption. Kuo et al....
SpeakOn's dictation device is a good idea marred by platform limitations
This $129 device uses MagSafe to stick on the back of an iPhone to power transcription across apps
Avec's Tinder-styled email app allows you to swipe through your inbox
Users can use the in-built voice transcription tool to reply to emails
Google has launched a free, offline AI dictation app that will automatically polish your speech.
Google AI Edge Eloquent is a new live AI transcription app that requires no subscription and has no usage limits. When you finish speaking, it will also filter out filler words like “um.” It’s currently only on iOS, but Google plans to bring the app to Android and macOS. [Image: https://platform.theverge.com/wp-content/uploads/sites/2/2026/04/google-ai-edge-eloquent-app-store.jpg?quality=90&strip=all]
Microsoft releases new AI models: competition with OpenAI ramps up
Microsoft AI has made its in-house models for transcription, speech recognition, and image generation available on Foundry.
Microsoft’s new ‘superintelligence’ game plan is all about business
Its new transcription model is a step towards those goals, says Microsoft AI’s Mustafa Suleyman.
Book Review: ‘Transcription,’ by Ben Lerner
In “Transcription,” Ben Lerner considers a famous father, a loyal protégé and a distant son, bound by devotion and separated by miscommunication.
Your Thymus and Your Healthspan
Our thymus gland plays a central role in the development or our immune system, specifically for supporting T cell development (how these cells got their name, maturation and differentiation in the thymus) and discriminating between self and foreign, non-self antigen proteins with production of dendritic cells. As we age, our thymus gland shrinks—the process known as involution—with progressive change from spongy to fatty tissue, with loss of functionality. But this process, with respect to timeline and extent, markedly varies from one person to the next. And to make things even more complicated, our thymus gland anatomy and precise location in the chest also is highly variable. So the famous Frank Netter diagrams from the 1960s (such as at left below) don’t capture the remarkable heterogeneity that a random set of 12 chest CT scans (below at right). What I consider as 2 landmark papers in Nature this week (here and here) used AI to quantify health of the thymus in 2 large cohorts, and then correlate the metric to a broad array of health outcomes. In this edition of Ground Truths, I’m going to cover three questions: (1) How was thymus health determined by AI?; (2) How is thymus health linked to key clinical outcomes? and (3) Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? Subscribe 1. How was thymus health determined by AI? This was accomplished by extensive work developing and validating an AI pipeline for 2 stages, the first for localization and segmentation of the thymus bed, and the second to quantify a digital marker, termed the thymic health score. There’s a lot to this algorithmic development, so I won’t go into all the details, but just provide a rudimentary outline of what was done. The 1st stage used supervised learning with 2 radiologists reviewing 2,461 chest CT scans. That work trained a 3D U-Net model to automatically identify the thymic bed’s 3D cropped region using center of mass coordinates, which reached 99.8% accuracy. The 2nd stage used a foundation model that was pre-trained with SwAV (which stands for Swapping Assignment between multiple Views), a self-supervised model, that generated a high-dimensional thymus representation of 4,096 features. That compares to the radiology reductionist and subjective scoring of 0 to 3 where 0 means the thymus is fully degenerated and fatty, and 3 is considered dense, intact glandular soft tissue. Notably, the self-supervised learning (SSL) performance was superior to supervised (AUC ~0.75 vs 0.55, respectively) reflecting the shallowness of the 0-3 classifier vs SSL’s holistic, self-taught AI. The thymic health score ranged from 0 to 100, with the highest number indexed to fully preserved thymic health. The algorithmic work extended to explainability with both Shapely value distribution, meaning the model was holistic not relying on any “magic” pixel, and occlusion sensitivity, demonstrating the model’s performance was not affected by ribs, sternum, lung tissue, but rather focused on the thymic bed directly. Below are a few saliency maps from the occlusion sensitivity that indicate the thymic bed focus, not affected by neighboring structures, using the jet color scale. Now the AI was ready for processing ~25,000 CT scans, each over 30 MB files, from the 2 large participant cohorts to provide a thymic health score, it did so in less than 14 hours, which is less than 2 seconds per scan! Share 2. How is thymus health linked to key clinical outcomes? The two cohorts were the National Lung Screening Trial, NLST (N=25,031) and the Framingham Heart Study, FHS (N=2,581) each with baseline demographics and long term follow up of >12 years for health outcomes. From the NSLT, you can see below that increased age and body-mass index were correlated to reduced thymic health. And, overall, men had reduced thymic health scores compared with women. There are a lot of graphs in the paper for outcomes, for both the NLST and FHS cohorts. To simplify the major outcomes, below is a composite Figure with striking reduction of all-cause mortality and for the different causes of death. The results were consistent between the 2 cohorts. For example, the cardiovascular mortality hazard ratio average was 0.57 in NLST and 0.38 in FHS (weighted to be 0.53 for the aggregate). The reduction of mortality also extended to digestive diseases and pulmonary disease (data not shown below). Lung cancer incidence was reduced by 36% for high vs low thymic health (Figure below, with a panel -incidence and b panel-mortality, adjusted for age, sex, BMI, smoking status). Notably, there was a smoker’s paradox: lower incidence and improved survival for lung cancer in smokers who had a high thymus health score. Smoking was associated with lower thymic scores whereas alcohol was not. Higher thymic health was linked to higher HDL cholesterol, lower triglycerides, lower fasting blood glucose, and lower systolic and diastolic blood pressure. Inflammation biomarkers, such as C-reactive protein and interleukin-6, were elevated in the people with lower thymic health scores. In their second paper, the same team looked at the relationship between thymic score and outcomes for 3,476 patients receiving cancer immunotherapy. The non-small cell lung cancer progression-free survival was reduced in patients with low thymic health score. A parallel relationship for survival was seen for other types of cancer including melanoma, breast, and kidney with a 44% lower risk among high thymic scores (Figure). A similar pattern was seen with different immune checkpoint inhibitors. The thymus health score outperformed programmed death ligand-1 (PD-L1)and tumor mutation burden (TMB) assay of the tumor and was an independent prognostic marker of progression-free survival. In this dataset, a direct connect with thymus score and adaptive immune function was noted with a correlation before cancer treatment for both T-cell diversity and thymus T-cell production (a metric known as T cell receptor excision circles). Thymus Removal Study There is a highly relevant citation about thymus function before moving onto ways to rejuvenate it. In 2023, a very important study of thymus removal during cardiothoracic surgery was published, with 1146 patients undergoing thymus removal vs 1146 matched controls (mean age 55 years). The adverse outcomes for thymus removal were striking, with a 2.9 higher risk of all-cause mortality and doubling of cancer incidence, 1.5 fold increase in cancer mortality, and 1.5-fold increase in autoimmune diseases. The immune function showed marked compromise after thymus removal, as reflected by CD4+ and CD8+ T cells (Figure below) Share Ground Truths 3. Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? In recent months we’ve learned a lot about the process of thymus involution and the pathways by which this may be modulated. Thymus involution is primarily due to loss to thymus epithelial cells (TECs) and there are 2 subtypes with different functions: the cortical, responsible for positive selection of T cells, and the medullary, for negative selection. When adipose tissue infiltrates the thymus, thymic adipocytes are pro-inflammatory, knocking out T-cell output. Likewise, systemic inflammation, or “inflammaging,” from smoking, obesity, and chronic stress promote thymic adipocytes. Now, from preclinical studies, we know about key pathways that account for these processes. Historically, back in 2014, FOXN1 was recognized as a single master transcription factor essential for TEC function, with studies in mice with forced FOXN1 upregulation leading to thymus regeneration. That laid the foundation for potential regrowth of quiescent thymus cells. It took awhile to find pathways to accomplish this goal and to even refute its role as the master regulator. The Liver-Thymus Axis Feng Zhang and his team recently showed that injection of an mRNA vaccine to the liver encoding DLL1, IL-7 and FLT3-L in combination, factors known to support thymopoiesis (Figure), successfully enhanced immune function in aged mice. However, the effect was transient. The FGF21 Story Two reports in 2025 addressed the thymus gland’s production of FGF21, a growth factor (fibroblast growth factor 21) and its control of thymus involution. This growth factor is also produced by the liver, but it doesn’t have impact on the thymus in aged rodent models. In contrast, The liver’s hepatocyte growth factor (HGF) has been shown to reverse senescent TEC structural changes. Growth hormone stimulates production of insulin growth factor-1 (IGF-1) in the liver and the thymus. Two small studies in human participants (TRIIM, for Thymus Regeneration, Immunorestoration, and Insulin Mitigation) of 6 and 50 people, respectively, treated with combined human growth hormone, metformin and DHEA, suggested the potential of slowing epigenetic aging and improving thymus mass and function. But the combination of drugs, small sample, and lack of controls make conclusions murky. Increased thymus FGF21 led to increased CD8 T cells in old mice and extended healthspan and improved physical performance. Building on the previous FOXN1 data, ablation of β-klotho, the obligatory co-receptor for FOXN1, accelerated thymic aging. The benefit to FGF21 was confirmed in a companion paper using an FGF21 knock-in mouse model showing thymus enlargement and increased TECs throughout the lifespan. (schematic Figure below). The accompanying editorial for these 2 papers speculated: “The proposed link between age-associated thymus involution and organismal aging is intriguing, and suggests we might seek to achieve systemic rejuvenation by counteracting thymic involution.” Other Factors Lessons from the Axolotl (Mexican Salamander) In an elegant set of experiments of the axolotl (Figure), known for its complete thymus regeneration after total surgical removal, mediators were identified. Surprisingly FOXN1 was dispensable. But midkine, a growth factor, appeared to be the driver, the initiator of thymus cell growth, survival, and repair. Other components that contributed were Postn+ (periostin-expressing mesenchymal niches) and Ccl19, a chemokine protein from the bloodstream. RANK and RANKL RANK (receptor activator of nuclear factor κB its ligand (RANKL) have been considered key regulators of medullary TECs. In a study of both aged mice and human thymus cell cultures, their key role was confirmed, with multiple benefits of resorting TEC function, recruitment of progenitor cells, and T cell development. Subscribe Summing Up This body of work strongly supports the health of the thymus gland as a critical regulator of human healthspan, not just a correlate or link. The new landmark studies are reinforced by the regenerative biology experimental models that have shown, via an array of mediators, that healthspan of aged mice is at least in part dependent on thymus gland function and its critical role for maintaining adaptive immunity. It sure seems that we’d be better off having an immune reservoir of naive T cells instead of a profile in older adults of exhausted, low quality, memory T cells, with a senescent phenotype. It is striking that we ignored the importance of the thymus gland for many decades. A wake-up call was the results of the thymectomy matched control study reviewed here, with the opposite of high thymic health score improved health outcomes. The convergence of AI and healthspan here is notable. The exceptional and laborious work for developing and validating (no less explaining) the AI to quantify thymus health set the foundation for probing the connect the major health outcomes in two cohorts with extensive follow-up. We’ve never had a way to meaningfully quantify the thymus gland before, so this represents important leverage of supervised, self-supervised, and transformer models. The study wouldn’t have been possible without AI. And it begs the question as to whether there are ways we can maintain our thymus at a high health score. But it’s not so simple to rejuvenate our thymus. There are multiple risks including the induction of autoimmunity, increasing the risk of cancer, and inducing a pro-inflammatory state. For example, factors that increase TEC proliferation could compromise the medulllary negative selection process and leak out auto-reactive (self-attacking) T cells. Thymic cells could be induced to proliferate, but we know, for example, that growth hormone and IGF-1 are associated with an increase risk of cancer. If thymus rejuvenation doesn’t clear out the accumulated senescent cells in older adults, then inflammation within the gland could block the production of TECs. Keeping these risks in mind, we now have identified many ways to keep our thymus healthy as we age that undoubtedly will be tested in clinical trials going forward. Ultimately, the benefit-to-risk tradeoffs will be defined. In the meantime, we have desperately needed an immunome. As I’ve stressed in multiple prior Ground Truths, we have no test in the clinic to assess a patient’s immune status! It was very encouraging for me to get an email from Hugo Aerts, the senior author of the landmark papers in the days after they were published: “I also wanted to say that your Substack on “Why We Need an Immunome” was inspiring for this work. We found it a very compelling perspective and greatly enjoyed reading it.” Just having an assessment of a person’s immune status via a chest CT scan, with millions of these performed per year, might help in guiding the right immunotherapy for cancer (e.g. more intensive, combinations for those with low thymic health scores) and help define people who are increased risk for age-related diseases of cancer, cardiovascular, and neurodegenerative. The main theme of Super Agers is that we now have many layers of data (genetics, proteins, biomarkers, organ clocks that can be integrated via multimodal AI) for us to define a person’s specific risk decades before one of these age-related diseases leads to symptoms, enabling prevention. From the new studies this week, we can add thymus health score as yet another way to understand a person’s risk, a window into their adaptive immune system and healthspan. And perhaps someday we will be able to safely rejuvenate the thymus, or maintain its health through one’s life, and use the thymus health score to monitor. NB: I wrote this post (No A.I.) A Quick Poll Loading... ********************************************************************* Thanks to Ground Truths subscribers (now > 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Share Ground Truths Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Leave a comment Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. 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