Over the years at WSJ, I relied on Joanna’s reviews of technology for many purchases (and things I avoided) reflecting her keen and brutal assessments. I also had fun working with her on some of her video assessments of health technologies.

Her book I AM NOT A ROBOT is both hilarious and highly informative. It is a terrific primer for those who are not fully grounded in AI getting into the history of AI and right up to date with generative AI’s progress.

To get a sense for why AI thought she was the next Tina Fey, check out the back cover! No surprise she got me laughing hard throughout the conversation, no less while reading the book.

Subscribe now

Here is a short YouTube video she posted on her All In AI year of 2025, referred to during the podcast.

Much of her testing of >100 AI products related to medicine and health care, which is what we especially got into during our conversation. She has 3 major rules in her assessment of AI: (1) Ruthless testing; (2) Benchmark vs human; and (3) Costs, which include “compute cost” that we discussed.

Here are some of the things we covered:

1. AI of her blood work

2. AI of mammogram and breast ultrasound, and overall experience as a person with increased risk of breast cancer

3. AI at the dentist (and ”Dentist Deep Clean”)

4. Assessment of Dr. GPT

5. Bill Gates on health AI

6. Her AI Trainer (Chris)

7. Waymo vs Uber

8. Her AI Therapist (Ash)

9. Nothing Bot Sex (her 2 digital lovers)

10. Impact on her children (including 6 Fucking Hamsters, the robodog Sirius)

A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, 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. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths.

Thank you , , , , , and >400 others for tuning into my live video with ! Join me for my next live video in the app.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

Subscribe now

The DL Era of Medical AI

Beginning in 2018, we started to take note that the retina fundus photo, or optical coherence tomography (OCT), had far more information embedded in it when “seen” by AI that was not detected by ophthalmologists. This led to the realization that supervised learning of hundreds of thousands to millions of images yielded superhuman vision. Many papers were subsequently published about AI of the retina image that supported it as a gateway to nearly every organ of the body, no less to the risk of Parkinson’s and Alzheimer’s disease many years before any symptoms appeared. These were each derived from single deep learning models probing the ability for the image to predict a certain condition. I gave a TED talk about this in 2023. A few years ago, Pearse Keane and colleagues published the first retina foundation model, a generalized dataset with many downstream tasks, called (RETFound) from 1.6 million images, demonstrating its prediction of heart disease, stroke, glaucoma, and Parkinson’s disease. This week, a new retinal image foundation model (Reti-Pioneer) from over 100,000 photos was published, adding thyroid disease, gout, and osteoporosis to the long list of conditions, beyond previously established Type 2 diabetes, hypertension, and hyperlipidemia, for determination of level of risk (summarized in the Figure). Who would have thought a retina image was this rich?!

Most people get an eye exam each year or every other year, which typically includes a photo of the retina. More than half Americans had an eye exam last year, or well over 100 million people. Yet none of the extraordinary progress that has been published for superhuman vision of the retina has been incorporated into routine medical practice!

Despite the lack of general use of AI of the retina, at least 4 companies have moved ahead to provide specific results for patients, although sparsely accessible or used in the United States. There’s Optain for cardiovascular risk, Toku Eyes for chronic kidney disease risk and biological age, Mediwhale for cardiovascular and kidney risk, and i-Cognitio Sciences (based in Hong Kong) for Alzheimer’s risk. Although the accuracy of risk of the various conditions is not 100% (= area under the receiver operating characteristic, AUROC of 1.0) this information could be provided for >15 conditions at a nominal cost ($1) or free to all people having an eye exam. But lack of any orchestration of implementing this huge body of work and evidence and issues such as reimbursement have held it back. It’s software that could and should be easily be applied to every retinal image, and someday ought to be part of a “medical selfie” that we could do with automated capture of the fundus using our smartphone and an app readout.

Last week, an AI to detect pancreatic cancer was published which detected ductal adenocarcinoma (PDA) up to 3 years ahead of radiologists (median advance interval 475 days) and the detection of occult PDA almost doubled for AI compared with radiologists (73 vs 39%, respectively, Figure below). The multicenter study also had external validation. Yesterday, the FDA gave approval for access to an experimental drug for pancreatic cancer with very promising results. How about access to an AI to detect pancreatic cancer before it would be picked up clinically?

In China, AI detection of pancreatic cancer via chest and abdominal CT is becoming routine using their validated AI tool known as PANDA. That is to say, the AI is automatically used for detection even though the scan was ordered for something else. That is essence for what has become known as Opportunistic AI. Some examples are shown in the Figure below.

There is a long list of missed imaging opportunities that I’ve summarized in the Table. Just a few weeks ago, as I wrote in a Ground Truths, there’s the ability to obtain a thymus health score via AI of a low resolution chest CT. To get critical information about our immune system health which is not clinically obtainable. We’re leaving so much valuable medical information on the table by not incorporating validated means of AI detection to our medical scans. That doesn’t even take into account what is encoded in electrocardiograms, pathology slides, and many other types of medical images that we’re not extracting with AI.

Share Ground Truths

The LLM Era of Medical AI

In the April issue, the editors in Nature Medicine published this essay calling for evidence. It reminded me of the famous Cuba Gooding line “Show me the money” from the Jerry Maguire movie.

As opposed to many randomized trials and prospective assessment with external validation of medical image AI, the evidence with generative AI in medicine is lacking. That has not held back the public or physicians from using AI chatbots and LLMs. For the public, according to multiple surveys, 12% of adults are using an AI chatbot every day, or about 40 million people, and estimates range widely from 32% to 73% for having used a chatbot for health information in the past year. According to a recent survey by the American Medical Association in March 2026 of 1,700 doctors, 72% are using genAI for at least 1 use case, and 35% for direct patient care, that is non-administrative, decision making. The graph below extrapolates that for ~1 million physicians.

The next graph indicates the projected use by physicians (from the AMA survey) by the end of 2026. You can see expectations are far different than current use! Note the plan for diagnosis assist.

For AI based decision support, such as making a diagnosis or optimal management of patients by clinicians, what is the evidence? We don’t really have any real-world data. This week in Science Magazine multiple (6) experiments assessing 2 LLMs (Open AI’s o1 and ChatGPT 4) and physicians for case vignettes supported the potential of improved reasoning and, in a simulation of real world emergency room decisions at 3 touchpoints (graph right below) compared with 2 doctors, there was improved initial triage decisions for 01. Most of the many publications use case studies, simulations, and actors as patients. Hardly representative of the messy world of the practice of medicine.

Share

On the patient side, there’s the same deficiency. A limited exception was a small, prospective, single arm study of 100 adult patients (preprint published comparing a model (AIME) vs primary care physicians for differential diagnosis and management plan, which were shown to be on par. A study of ChatGPT Health for helping to triage patients (simulated) to stay home or go to the emergency room did not fare well for the AI, with many blatant triage errors for real emergencies (such as diabetic ketoacidosis or impending respiratory failure (Figure).

In a randomized trial of LLMs comparing patients assisted by LLMs for 10 medical scenarios (not real-world), the patients did’t do well (Figure) and the conclusion was “We recommend systematic human user testing to evaluate interactive capabilities before public deployments in healthcare.”

There are a couple of exceptions to the lack of real world assessment including a Nature Health paper for use of an LLM in 16 primary care clinics in Kenya and a single center randomized trial in eye care. The latter found a higher diagnostic rate for ophthalmologists using AI (92.2%) compared with those who didn’t (75.4%).

In summary, there is very little evidence for LLMs benefiting patients or doctors for health outcomes. That is not to say that generative AI doesn’t help. It offers strong support for administrative work, such as summarizing charts for doctors, or reviewing labs for patients, or providing relevant publications to clinicians and patients, or helping with pre-authorizations for doctors and billing questions for patients. AI chatbots are helping patients prepare for visits, understand their diagnosis and prescriptions.

But going back to the Nature Medicine’s call out for evidence, we need it. For LLMs to help doctors make critical diagnoses or treatment decisions, that requires prospective studies, ideally randomized, but at the very least rigorous and large, with independent adjudication of health outcomes. And for the public, how do we know entering all one’s data leads to the correct diagnosis or treatment? This week we learned that the symptom quality reported to an AI was deficient as compared to that presented to a physician. How does the benefit of patient access to genAI compare with potential harm?

Summing Up

I’ve reviewed a major paradox whereby AI for medical images, with extensive research dating back more than a decade ago, is not being implemented. Whether it’s a mammogram, a CT scan, a retinal image, or colonoscopy, that have all been extensively studied, their value to improve accuracy and risk assessment in medicine is being missed and essentially disregarded.

On the other hand, tens of millions of Americans are using AI chatbots for medical support, as are a substantial proportion of physicians. There are many reasons to use AI here that are easy to support, because they represent an extension of a web/Google search. Just with much more specificity and depth of response, not something that would be subject to regulatory oversight. But when it comes to making a diagnosis or providing a treatment plan there needs to be proof that LLMs are improving accuracy and outcomes. We’ve already seen multiple studies (again not real world) when the AI performed better for various tasks than the doctor with AI, including the new Science paper this week, indicating we don’t even know yet the optimal way of deploying AI (the human-in-the-loop question). As Raj Manrai wrote in his excellent explainer thread, as one of the senior co-authors of the Science paper: “What do our results actually call for? Prospective clinical trials. Health systems investing in infrastructure now. Monitoring frameworks that track not just diagnostic accuracy but safety, efficiency, and cost. The science has reached a point where trials are justified.” We can’t get to high performance medicine, relying on generative AI for key decisions, without that.

One sticking point. Unfortunately, by the time peer review papers are published, the models assessed are outdated (such as 01, which is text-only, when GPT5.5, which is multimodal, would be current). That can give the AI enthusiasts cover, saying the lack of optimal AI performance was because of a weak and old model. The reality, however, is to prove it. Publish it quickly as a preprint.

We’re just a couple of years into the LLM era for medicine. Waymo started in 2009 and it took more than 15 years of rigorous, iterative work to show its true superhuman performance for outcomes with >90% reduction of serious accidents compared with human drivers. Let’s fix this paradox of medical AI implementation. It’s a two-fold and major undertaking. Amping up the use of medical AI where it’s proven and performing the clinical trials required to justify wide-scale adoption where pivotal evidence is lacking.

NB This post was written by me, no AI. Two images were made with the help of AI, as indicated. I have no COI related to the content of the post.

A big thanks to Ground Truths subscribers (> 205,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, 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. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in throughGround Truths.

For those of you interested in extending healthspan, my NPR segment this week

“You are a slightly different genetic version of yourself today from yesterday, and will be different yet again tomorrow.”—Roxanne Khamsi

Roxanne Khamsi is one of the leading life science journalists, a contributing writer at The Atlantic, recognized with multiple awards for notable publications. Her new book is entitled BEYOND INHERITANCE. It tells the story about us all being genetic mosaics, chock full of somatic (acquired) mutations, and the implications of those mutations for our health. The myth of a single genome, carbon copy, master blueprint, but instead a dynamic, shifting mosaic in constant internal evolution.

Share Ground Truths

And here’s the back cover. I was delighted to endorse this book, and reread it to prepare for our podcast. It’s extraordinary and mind-bending.

Here are the topics we covered:

—The Math. 330 billion cells of our ~37 trillion turnover each day, which yields trillions of mutations per day.

—Cellular competition. Winners and losers of an “endoevolution,” Darwinian selection inside us whereby healthy or super-fit mutated cells can crowd out the unfit ones.

This was theorized in 1881 in a book THE STRUGGLE OF PARTS, by Wilhelm Roux

which led to Friedrich Nietzsche’s famous quote “Uniformity is pure delirium.”

Subscribe now

—Single-cell sequencing. How this field catapulted forward owing to the ability to zoom in on genomic mutations at the cellular level.

—Cancer chemotherapy overkill. The routine scorched earth, carpet bombing approach can promote resistance and deleterious mutations, leading to an adaptive strategy of leaving some cancer cells behind, as has been shown to be effective in prostate cancer for improving survival.

—The immune system somatic hypermutation. B cells have the theoretical capacity to produce 1 quintillion unique antibodies (a million trillion). If this weren’t possible, we could die from a common cold. In the Covid pandemic, even before the Omicron variant appeared, Covid booster shots induced hundreds of unique antibodies with neutralization capacity against Omicron. The anticipatory “Red Queen” effect.

—Autocorrection of mutations. They can revert, cure a rare genetic disease from within. It can be considered “Natural Gene Therapy.” Example below of a skin condition Epidermolysis Bullosa with revertant mutations (→ normal skin appearance)

—Different role of acquired mutations through the lifespan. Examples: At embryonic stage, Lines of Blaschko (Image below). In mid-life endometriosis, and in older adults Loss of the Y chromosome (LOY) and Clonal Hematopoiesis of Indeterminate Potential (CHIP). Note these 2 somatic mutation clone conditions are associated with risk of diseases; CHIP-cardiovascular and cancer; LOY-heart failure and Alzheimer’s. I’ve written about CHIP extensively here and here.

—Phenocopy. How a somatic mutation can look the same as a germ-line, inherited mutation, with respect to a disease, and how that is determined.

—Environmental effects inducing somatic mutations: UV light, air pollution, plastics

Share

—and 3 new papers in the past week!

1. Somatic mutations in the microglia cells of the brain, same as cancer mutations, drive inflammation and are enriched in the Alzheimer’s brain

   

   2.. The potential of “promolytic drugs” to be used to prevent cancer in people who exhibit precancerous somatic mutations

   

   3. How somatic mutations can be the basis of autoimmune diseases

We also spoke about the role of somatic mutations in aging and super aging

A related excerpt at The Atlantic

A Quick Poll

Thank you , , , , , and more than 500 others for tuning into my live video with ! Join me for my next live video in the app.

And a big thanks to Ground Truths subscribers (> 205,000) 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. We just accepted 51 interns for the 2026 summer, a new record, from thousands of high school, college, and med school student applicants. Our fully loaded cost to do this program is ~$300,000 per year. We’re deeply appreciative for your support of Ground Truths that has enabled this program to prosper and expand.

One more thing:

SUPER AGERS was featured on the CBS Morning Show this week in a segment with Dr. Jonathan LaPook, Chief Medical Correspondent, on the meaning and measurement of biological aging.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

This is one of my favorite books over recent years. Sebastian Mallaby is the Paul A. Cocker Senior Fellow for International Economics at the Council of Foreign Relations and author of 6 bestselling books.

THE INFINITY MACHINE tells the story of AI’s progress over the past 15 years largely, but not exclusively, from Demis Hassabis as the protagonist and leader of DeepMind’, with its 2010 mission statement to achieve superintelligence by 2030. It’s a rich, informative, page turner.

Subscribe now

What We Discussed:

—What is an Infinity Machine?

—Influence of Claude Shannon’s Information Theory and Douglas Hofstadter’s Pulitzer Prize winning book Gödel, Escher, Bach

—Origin of DeepMind in 2010. Prescient. Charter, business plan, included use of agents. How Demis Hassabis was made for the mission!

—Contrasts with Sam Altman and the other AI leaders, the Oligopoly (cover of The Economist this week). For example, Nature papers vs white papers on company websites.

—In March 2016, the same day when DeepMind’s AlphaGo beat Lee Sedol, Hassabis says it’s time to do protein folding (later known as AlphaFold).

—Symbolic AI (historic, deductive, rule-based) vs Deep Learning (Toronto tribe) and Reinforcement Learning (Alberta tribe).

—The Big Miss: DeepMind’s lack of early recognition of the importance of transformer models (leading to ChatGPT), creating a big opening for OpenAI. And why was this missed? The Comeback Story. Is this happening again with coding (not in the book)?

—The AI Arms Race and Hyperscaling

—How the complex relationship between Google and DeepMind evolved

—The Double Cross

—With the dangers anticipated (parallels to Oppenheimer, Manhattan Project, and the atomic bomb), how to promote AI safety?

—Is the major build up of data centers justified?

Thank you , , , , , and more than 600 others for tuning into our live video with ! Join me for my next live video in the app.

And a big thanks to Ground Truths subscribers (> 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

And, if you’re interested on extending healthspan, two recent podcasts/TV segments on SUPER AGERS

On With Kara Swisher

On PBS

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

Subscribe now

Here’s a quote from Trisha early in the book:

“I’m not a wellness guru. I’m a scientist.”

Another quote from a Vanderbilt professor:

“An effortless, socially appropriately timed bowel movement is the second greatest bodily pleasure known to man.”

Share

The proportion of people with bowel issues is remarkable, a brief summary:

Some of the topics covered in our lively, fun and highly informative conversation:

—The 3 P’s Propulsion, Pliability, Pelvic Floor

—Ten Myths

—99% of farts have no odor; the 1% that do are from hydrogen sulfide, Pepto-Bismol substantially reduces the latter (and an incredible experiment of people with rectal tubes and judges smelling their gas)

—What is the normal frequency of pooping?

—the Bristol Scale of poop appearance and what it means

—Transit time

—The uselessness and danger of bowel cleanses

—Fibermaxxing

—5 minutes max on the toilet and positions to help propulsion

—Psyllium and laxatives

—The art of wiping and bidets

—Fecal incontinence

—Not to miss urges and the TRPV1 and PIEZO2 receptors

—Impact of coffee, alcohol, NSAIDs (Ibuprofen, aspirin, naproxen, etc), and hydration

—What are the different definitions of constipation?

—What gives poop its color?

********************************************

Subscribe now

Thank you , , , , , and >600 others for tuning into our live video with ! Join me for my next live video and newsletters in the app.

And a big thanks to Ground Truths subscribers (> 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

Adrian is a molecular biologist and co-founder and CEO of Genyro, a synthetic biology company. He has published 2 previous books on life science (Life Without Genes and An Intelligent Person’s Guide to Genetics). In this conversation we discussed his new book, cover below and the title of this post.

Subscribe now

ABI. As Adrian puts it, a monumental shift, a second genesis, the “artivolution,” ability to use a molecular Gutenberg press, it’s post-Darwinian.

I made an infographic about the book and our conversation with NotebookLM

The expansion of genome sequences beyond “Fred’s library” (referring to Fred Sanger, father of genome sequencing, little green box)

We talked about the jump from DNA reading to editing and now writing genomes, with the potential of the latter for both good and harm. I disagreed with Adrian about the bright prospects for curing diseases, but there are many possibilities for positive impact, such as intervening vs the climate crisis and sustainability.

We also discussed the large language of life models (LLLMs) and by coincidence my colleagues and I just published a review of these in this Nature Biotechnology (←free access is hyperlinked).

“It should be possible to meet most of humanity’s needs through biologically inspired designs—to solve many global problems, revolutionize health care, extend human lifespan, and create other organisms to order.”—Adrian Woolfson

If you are into life science, I think you’ll find Adrian’s book thoughtful and provocative, even if you don’t agree with some of his optimism like a disease-free organism.

The topic connects with digital biology, a theme that is approached in many editions of Ground Truths, such as this one with Patrick Hsu

***************************************************

Thank you , , , , , and more than 600 others for tuning into my live video with ! Join me for my next live video in the app.

And a big thanks to Ground Truths subscribers (> 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

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 now

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 now

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. From a practical standpoint, with 20 million chest CT scans performed each year in the United States, opportunistic AI-derived thymic health scores could be routinely provided as part of their interpretation.

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

*********************************************************************

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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Nearly 2 years ago here in Ground Truths (GT) I wrote “The Under-Appreciation of CHIP” calling out the need to take this assay seriously because it conveyed substantial risk information, independent of traditional factors, for cardiovascular disease, cancer, blood clots, and other conditions. If you are interested in this topic (and I hope you will be), I suggest you go back and read that post because I won’t review much of the background here, just a little. In this edition of GT, I’m going to summarize substantial new data on CHIP, review my results, and call for action.

Share Ground Truths

Quick Background

CHIP is the acronym for clonal hematopoiesis of indeterminate potential. It refers to the acquired (somatic) mutation of a blood stem cell that gives it fitness for clonal expansion, with a clone size abnormality cutoff defined as 2% or greater of blood cells, or specifically a variant allele frequency (VAF) ≥ 2% of a white blood cell driver mutation.

CHIP increases with aging: only 2% of people age 50-69, 10% age 70-79, 20% age 80-89, and >39% age 90+. The most common mutations are DNMT3A, about 48%, TET2, about 22%, ASXL1 11%, and a group of others (such as JAK2, TP53, SF3B1) at 19%. The 3 most common are mutations in epigenetic (methylation side chain, chromatin, regulator) genes.

The presence of CHIP is associated with many disease, especially cardiovascular, cancer, and inflammatory conditions, and the risk increases with higher CHIP frequency.

Last month the American Heart Association published a scientific statement about CHIP: “CH is increasingly recognized as a potential driver of cardiovascular disease.”

Below is the key Figure from that review. Besides advanced age there are other risk factors for developing CHIP. Whit CHIP ≥ 2%, the link with higher levels of inflammation and immune dysfunction, in the context of advanced age, referred to as inflammaging and immunosenescence, is seen. As is the association to multiple cardiovascular diseases and blood cancers. While only 0.5 to 1.0% of people with CHIP > 10% will develop a blood cancer each year, the dysfunction of the immune system and a chronic pro-inflammatory state are detected without disease manifestation. In patients with advanced solid cancers, over 25% have CHIP, much higher than age-matched healthy control individuals.

As reviewed in my previous post on CHIP, the cardiovascular disease hazard ratio for CHIP of 1.8 which exceeds smoking, hypertension, and total cholesterol >200 mg/dl (all at 1.4). A new CHIP risk score has recently been proposed that adds to CHIP status by partitioning CHIP level of risk.

Share Ground Truths

New CHIP Findings

I’ll divide these into disease and treatment related reports, and point out this is not an exhaustive review but a sampling of new studies that strongly reinforce the importance of CHIP.

Here’s a Table of some recent disease related findings:

Let me provide a bit of color for these. For improved response to checkpoint therapy for non small cell lung cancer and colorectal cancer, tagged to TET2 mutations, the mechanism was probed below. Note that circulating CHIPs penetrate the tumor microenvironment and here TET2 mutant clones facilitate increased interferon and T-cell response.

But in a different study of TET2 mutant CHIP, in the presence of an aortic aneurysm, the pro-inflammatory macrophage effect was linked to accelerated aneurysm growth.

An important discovery for resilience to CHIP, protecting against its formation and related blood cancers, was the discovery of a gene variant on chromosome 17 in 3 large cohorts (Figure) linked to reduction of multiple subtypes of CHIP (driver mutations) and blood cancers. This turned out to be related to an RNA network and specifically down-regulation of the RNA binding protein MSI-2. This seminal finding could lead to a new intervention to suppress CHIP and its adverse health outcome impact.

Now let’s move on to some new treatment findings.

Low dose colchicine was shown to have a consistent effect of reducing CHIP in a randomized placebo-controlled trial with longitudinal sampling (Table).

This anti-inflammatory drug has previously been studied in the atherosclerotic murine model and patient cohorts with TET2 mutations to reduce plaque and heart attacks, respectively.

Beyond colchicine (an NLRP3 inflammasome blocker), the IL-1β–neutralizing antibody was shown to reduce events in participants with TET2 in a randomized trial and other potential interventions have been reported such as metformin (vs DNMT3A), Vitamin C (vs.TET2), inhibitors to other interleukins such as IL-6, or inflammasome blockers (Figure). The NLRP3 inflammasome inhibitor selnoflast is being assessed in an ongoing clinical trial for CHIP. Even GLP-1 drugs, known to have portent anti-inflammatory action, have recently been raised as a potential effective anti-CHIP intervention. I should mention that low-dose colchicine, which has the best dataset to date, is remarkably cheap, pennies per day, generic, and well tolerated.

Subscribe now

My CHIP Results

In response to my post on CHIP a couple of years ago, a company (Lucence) offered to provide my CHIP results free of charge. I recently had the blood test and got back the results. My CH was 0.3%, well below the 2% threshold for diagnosis and the only driver mutations detected were in TET2 (4 different variants each at very low VAF). Compared with the general population, not adjusted by age, the result indicated a lower risk for the 3 major outcomes as shown below. In my age group, the chance of having CHIP (defined as >2%) is more than 10%, so I feel fortunate. Had I been found to have TET-2 CHIP I might have considered starting low-dose colchicine.

The Implications

We’re learning much more about CHIP, how it links to a risk of many diseases spanning cardiovascular, cancer, thromboembolic (clotting) and liver (previously reviewed in GT). Different driver mutations carry different risks, and even the same CHIP mutations, such as TET2, can do both harm (aneurysm growth) and good (improve response to soldi tumor immunotherapy). The fact that these are multiple clinical studies fully backed up by animal models supports evidence for causality. Some mutations, like DNMT3A, have been linked to improved survival in colon cancer, so the presence of CHIP is not always a bad sign. While JAK2 is an unusual subtype of CHIP (range 0.5 to 4% of CHIP driver mutations), it is specifically associated with clotting complications, such as pulmonary embolism.

The CHIP cause and effect relationship is not yet considered fully established but the new data from multiple parallel human and animal studies strongly support that CHIP is not just a link to adverse outcomes, that it is highly likely to be a driver.

So why don’t we have routine CHIP assays for people of older age? One reason would be we don’t have therapies that are effective, but that seems to be negated with low- dose colchicine and many other candidate drugs with promising data for effectiveness (either blocking CHIP formation or its downstream risk of diseases). Another reason is that CHIP is hard to assay accurately. While it can be detected by whole genome or whole exome sequencing, the gold standard is to use a narrow, targeted panel of ~100 genes and do very deep sequencing, exceeding 500X. That is what was used by Lucence to do my assay, but it has a charge of $950 which is extremely high and I consider untenable. With the marked reduction in sequencing costs in the last couple of years, getting a precise and accurate CHIP assay at low cost should be a priority, in conjunction with dedicated clinical trials of drugs that prove outcome improvements.

Another potential downside of CHIP lab tests is inducing anxiety, such as seen in cancer survivors, and others with high-risk results for major diseases. But the trade-off of close surveillance of such individuals and mitigation of risk factors deserves consideration. Getting ahead of a disease enables prevention, which is typically far better than resorting to a treatment.

With all this background, it is notable that there are currently 2 academic centers that have established dedicated CHIP Clinics, both the University of Chicago and Cleveland Clinic. After my initial post, I learned from Dr. Jennifer Kwan there is a hybrid cardio-oncology CHIP clinic at Yale Medicine. Why aren’t there more? With all the evidence that keeps accumulating, why aren’t we making CHIP assessment widely available at low cost for select individuals (such as 70+ years of age)? Our blood makers for inflammation, such as high-sensitivity C-reactive protein, are notoriously non-specific and can be misleading. I would like to change the CHIP acronym to Clonal Hemaotopoiesis of Important Potential, getting rid of the Indeterminate qualifier. It is certainly informative. I think more so than most of the hundreds of tests that companies like Function Health provide to their several hundred thousand customers. Like Lp(a), will it take another 8 years before we have new guidelines from cardiovascular, hematology and oncology professional societies that back up the utility of diagnosing and treating CHIP?

NB: I wrote this post with no AI assistance. I have no relationship with any company that does the CHIP assay or potential treatments that would treat CHIP.

**********************************************

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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Here are some of the topics we discussed and a few related hyperlinked citations:

—Importance of Deep Sleep (and her paper on what happens when deep sleep is purposely disrupted, how it is modulated, effect of alcohol

—The Orexin Antagonist drugs that promote sleep (and a study that shows they can reduce p-tau217 and other neuroinflammation markers

—Link of sleep regularity with less all-cause, cardiovascular, and cancer related mortality

Figure 3.9 from SUPER AGERS (SRI-sleep regularity index)

Share

More things we discussed:

—A sleep foundation model that predicts 130 diseases

—Impact of menopause on sleep

—Getting to sleep vs staying asleep

—Role of naps

—Impact of interruptions of sleep

—Sleep apnea and new interventions

—Vagal nerve stimulation and sleep

—Cerebrospinal fluid wave that occurs during attention lapse after poor sleep

—cognitive behavioral therapy for improved sleep

—Wearables, sleep scores, and effect on sleep

—Any supplements that help sleep?

—The rare genetically endowed short sleepers

Subscribe now

Thank you , , , , , and more than 600 others for tuning into my live video with ! Join me for my next live video in the app.

**************************************************

Thanks to Ground Truths subscribers (> 200,000) from every US state and 210 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

+++++++++++++++++++++++++++++

I also want to thank the National Academies of Science, Medicine and Engineering for their recent recognition.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

Subscribe now

How They Are Measured

Cardiorespiratory fitness (CRF) is a real world assessment of a person activities, such as walking or on a treadmill, a reflection of a person’s resting metabolic rate, measured in metabolic equivalent of task (MET) units with 3 recognized levels of intensity : Light (<3.0 METs), example slow walking; Moderate (3.0-5.9 METs), example brisk walking, 3-4 miles per hour; and vigorous intensity (>6.0 METs), example jogging. 1 MET is the energy used in sitting or resting; 10 METs requires 10-fold the energy expenditure. CRF integrates cardiovascular, lung and musculoskeletal functional capacity.

There are multiple methods to calculate your METS, including a standard treadmill MET chart (below left) that plots speed and incline, use a formula if you are doing the Bruce treadmill protocol or the chart below (right), or using heart rate (with any aerobic activity, such as bicycling or jogging) with the formula: METS=0.05 X heart rate+2. So if your HR got to 140 that would be 9 METS. For every increase in heart rate of 10 beats per minute, there’s about a 1 MET increase.

Maximal oxygen uptake (V02 max) is only accurately determined as a performance lab test with a metabolic cart, trained technicians, a specialized tightly fit mask that captures every molecule of inhaled oxygen and exhaled C02 on a ramped treadmill or stationary bike exercise protocol until absolute exhaustion. This is the ceiling of aerobic power achieved via direct gas exchange. A V02 max test costs about $150 for a standard assessment in a university lab.

V02 max by wearables are obviously not measured by gas exchange or directly, but instead through various imputations based upon population-based algorithms of heart rate and movement (GPS/accelerometry). Studies have assessed the Apple Watch, Garmin Fenix 6, and Fitbit with a mean absolute percentage error of 7-16%. Overall, they have been found to consistently underestimate V02 in fit people while overestimate in unfit individuals. They also rely on optical heart rate (which may be inaccurate in people of color), device positioning and wrist anatomy, and can be influenced by such factors as hydration status, altitude, and ambient temperature. Typically, a 6-minute walk is the basis for a wearable to provide the user a new V02 max result. That may not be at all representative of an individual’s exercise capacity.

Share

The Datasets For Assessment

Datasets for Cardiorespiratory Fitness

In JAMA 2009, a meta-analysis of 33 studies of cardiorespiratory fitness was published for the relationship to all-cause mortality in a total of 102,980 participants. A better CRF (per 1 MET higher) was linked with a lower all-cause mortality (Figure) and individuals who had achieved 7.9 METs had substantially less all-cause and cardiovascular mortality. One MET higher CRF was associated with a 14-15% reduction of mortality.

In 2016, the American Heart Association issued a scientific statement on CRF and asserted it should be regarded as a clinical vital sign, reviewing all of the published data to that point.

In 2018, Mandsager and colleagues from the Cleveland Clinic published their data from 122,007 consecutive patients who underwent exercise treadmill testing and had long term follow-up for outcomes.

Here is the Table of METS performance by age and sex. You can see there are 5 categories (columns) from low to elite.

All-cause mortality by sex and the 5 levels of performance are plotted below. The hazard ratio of 1.41 (about 40% increases risk of all-cause mortality) for above average vs below average was the same as the risk of smoking or diabetes. The hazard ratio for mortality from low to elite was more than 5-fold. The favorable impact for women beyond men for METS was seen for each performance group. These results were adjusted for potential confounding variables.

In 2022, Kokkinos and colleagues published CRF exercise treadmill data for over 750,000 veterans aged 30 to 95 years with a mean follow-up of 10.2 years. The analysis was based on 6 categories of MET performance but the hazard ratios were similar to the Cleveland Clinic data (e.g. extremely fit vs lowest 4-fold in this study, 5-fold hazard in the prior one).

Here is a good summary graph of that study. In both there was no risk of increased mortality at the highest fitness strata—in fact it was consistently lower for each age group.

Datasets for V02 Max

There are limited data for direct measurement of V02 max and outcomes. The 2001 Kuopio study from Finland of 1,294 men with 10.7 year follow-up did measure V02 max directly once at baseline along with a symptom-limited exercise tolerance test on a bicycle ergometer. The relationship of V02 max (by quartiles) to all-cause mortality is shown below.

In a 2024 meta-analysis of 42 studies with V02 max (categorized as “objectively measured CRF”) and estimated CRF for prediction or all-cause and cardiovascular mortality, the results were remarkably similar (cardiovascular mortality, 14% reduction, graph below) but notably there were 234-fold more participants with exercise CRF than by V02 max measurements, or >99% of the data is derived from METS. That is to say, nearly all the data we have for link to outcomes comes from CRF, not V02 max.

Reference standards have been published by age group for V02 max. For more information such as by sex, please check the link.

There are other specific studies in heart failure ,chronic obstructive pulmonary disease, pulmonary hypertension and pre-operative evaluation that show use of V02 max can help guide risk or treatment.

Share Ground Truths

Conflation and the V02 Max Craze

The leading proponent of using V02 max in recent years has been Peter Attia, through his podcast The Drive and book Outlive. He has consistently asserted “V02 max is the singular most powerful marker for longevity.” But the problem is conflation. He cites all of the studies of CRF without measuring V02 max and extrapolates to a V02 max result (see side-by-side Kokkinos study Table and Outlive Figure footnote below) and throughout his discussion of exercise in Chapter 11 of Outlive. For example, he writes: “this number [V02max] turns out to be highly correlated with longevity” citing all studies that did not measure V02 max.

In a recent YouTube video by Joseph Everett and Nick Norwitz entitled “Hidden Data: How the Top Longevity Doctor Tricked Us All” there is a segment about V02 max and this significant issue of conflation, discussed by Chris Masterjohn. Below is the relevant 6 minute clip within the longer video. It includes a bit of the 60 Minutes segment with CBS correspondent Nora O’Donnell doing a V02 max text and Peter’s assertion: “We don’t have a single metric of humans that we can measure that better predicts how long they will live than how high their V02 max is.”

As Masterjohn aptly points out, the fixation on V02 max, which is not actually supported by the data, also misses out on our ideal goal of diversity of exercise, including strength and balance training. Indeed, Kim et al, analyzing over 70,000 UK Biobank participants, for both CRF (submaximal bicycle test) and grip strength with all-cause mortality and concluded: “Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.”

Bottom Line

I’ve never done a V02 max and see no reason to do it with the issues of cost, inconvenience, and the pain. As Attia correctly states about going to maximal exhaustion to get V02 max: “If you’ve ever had this test done, you will know just how unpleasant it is.” For spartan, Olympic, high performance athletes who are in high intensity training, or in patients with heart failure or pulmonary hypertension there may be a place for serial V02 max measurements, providing highly objective “goal standard” physiologic metrics. Otherwise, there are no supportive data for people going out and getting a V02 max and making this the focus of their exercise training. That is the reason I didn’t even mention V02 max in my Super Agers book.

Nearly all of the relevant data related to outcomes are based on exercise on a treadmill or bicycle with METS as the index of cardiorespiratory fitness. We should not be placing much value on our smartwatch data. My Apple Watch gave me encouraging high V02 max data over 6 months to suggest my CRF is well above people in my age group (70+, see reference standards above) but I know the data are woefully unreliable.

The problem now, with so much misplaced hype on V02 max, is that most people are using their smartwatch output for gauging their cardiorespiratory fitness, like the 2 patients I mentioned at the top of the post. It’s free to calculate your METS! And that is the real basis of the relationship to all-cause and cardiovascular mortality that has been firmly established in the peer review literature. To be clear, Attia’s assertion is false: "V02 max is the single greatest predictor of your lifespan."

This problem surfaced recently with the introduction of ChatGPT Health. Geoffrey Fowler, the tech journalist at the Washington Post, submitted all his Apple Health and asked for an overall assessment of his health (actual prompt: “give me a single score (A-F) for my cardiovascular health over the last decade including component scores and an overall evaluation of my longevity.”) It gave him an “F.”

Then he gave ChatGPT Health his electric medical record access (portal) and asked the same question again. It gave him a “D’ and attributed that to his V02 max data of 34 ml/kg/min in the past year, below a 45-50 year old male! He also entered his Apple Watch data to Claude Health and it gave him a D+ status Specifically, Claude Health gave him a C- because his V02 max had declined from 41 to 32 ml/kg/min from 2016-2026. But he had over 7,500 steps/day throughout the decade.

These outputs are indicative of the problem—the unreliable wearable V02 max data have become unduly emphasized by current AI platforms using smartwatch data! That will only make the problem worse, adding to the confusion, conflation, and emphasis on the wrong metric.

I hope this post helps to sort out what we know and that the datasets for cardiorespiratory fitness, representing real world physical activity— not V02 max —are the basis of the link to improved survival and freedom from cardiovascular mortality.

If we’re going to focus on a metric it ought to be METS, not V02 max. Not only is it free, simple and universally available, but it is the one best studied for health outcomes. And perhaps the better strategy is to be as physically active as possible and not worry about any metric!

NB: No AI was used in any way to write this post. As mentioned in the caption, I got help from Gemini-3 to produce the first Figure. I have nothing to do, no COI, with any company working with cardiopulmonary fitness or V02 max.

********************************************************************

Thanks to Ground Truths subscribers (> 200,000) from every US state and 210 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Subscribe now

1, Improved Accuracy of Detection with Reduced Workload

The National Cancer Institute estimates that 20% of breast cancers are missed by mammograms, leaving plenty of room for the potential of AI to help.

The first study that caught my eye about the promise of AI for mammography interpretation dates back to 2019 from NYU with supervised learning of more than 1 million mammogram images and 14 radiologists. The area under the curve with AI, a performance metric, was 0.895 (1.0 is perfect) and the conclusion was: “We also show that a hybrid model, averaging the probability of malignancy predicted by a radiologist with a prediction of our neural network, is more accurate than either of the two separately.”

Since that time, retrospective studies of various AI algorithms were reported on a frequent basis. Then, in 2023, a real world of medicine study in Hungary with the Kheiron algorithm was published in Nature Medicine. Like MASAI’s design, comparing 2 radiologists vs 1 (or 2 for highest risk of 10 score) plus AI, it found enhanced detection of cancer, 83% of which are invasive.

Notably, there was a >30% reduction of radiologist’s workload. This report from Hungary led journalists to travel there and study their cancer screening clinics, where 5 were performing 35,000 screenings a year with AI since 2021. This article appeared on the front page of the NY Times in March 2023.

Screening in the US is different from European countries because it relies on a single radiologist. That raises the question as to whether the big workloadreduction would also be seen here. But use of AI to partition very low risk scans, a so-called “delegation strategy,” would be expected to achieve a substantial workload reduction in settings with a single radiologist.

With that background, let’s go on to the landmark MASAI trial results, initially reported last year. This trial used the Transpara algorithm, developed by ScreenPoint Medical in The Netherlands, with 2D mammography. Subsequently, on 30 January 2026 the two-year follow up was published. The Table below summarizes the main results for both reports.

From the screening phase, there was a 29% increase in detection of cancer with AI, with a 24% increase in invasive cancer. There was no significant difference in the recall rate. The false positive rate was 1.4% in both arms of the trial. There was a 44% reduction in screen-reading workload.

At 2-year follow up, there was 12% less interval cancer detected in the AI arm, and the cancers picked up by AI were smaller, less aggressive: 16% reduction of invasive cancers and a 27% reduction of non-luminal A subtypes (including triple-negative and HER2-positive cancers). Accordingly, the AI support served a preventative role for earlier detection, catching aggressive breast cancer at the time of screening. But there is more to AI and prevention as we’ll get to in the next section. Of note, the Transpara algorithm is being used in 2 other large randomized breast cancer screening trials: in Norway, a trial of 140,000 women, called AIMS and in the US with 400,000 women, known as PRISM.

Share Ground Truths

Back-up From Real World of Medicine Studies

Besides the prospective, real world study conducted in Hungary, a nationwide study in Germany reported on over 460,000 women undergoing AI-supported mammography reading (N=260,739) or without AI support (controls, N=201,079), with the finding of a 17.6% high rate of cancer detection. It used a different algorithm called Vara MG from a German company.

In the United States, a large study that compared AI-support of a single radiologist (N = 208,891) for what AI identified as “at-risk” (multistage AI-driven workflow) to a radiologist (controls, N = 370,692) there was a 21.6% increase in breast cancer detection rate. The AI used was from DeepHealth. The results were consistent across ancestries and breast density, as seen below.

Another single center, smaller (N-55,581) prospective study from Sweden also showed better detection with AI support, using a different algorithm called Insight MMG from Lunit.

In a prospective, real world multi-center assessment in over 25,000 women in South Korea, the use of AI support led to a significant increase in cancer detection with no rise in the recall rate.

All of the real world studies and MASAI showed no significant increased in the recall rate. That is to say, all of the benefit was accomplished without prompting more callbacks to women for something concerning about the scan.

2. Prevention of Breast Cancer

As you’ve seen above, as validated in the MASAI trial, AI support identified more of the aggressive cancers up front, and at 2-years of follow-up the results reinforced the advantage of increased early detection. But there is another dimension to preventing breast cancer: identifying risk in what is read out as a normal mammogram. in June 2025, CLARITY Breast received the first FDA de novo authorization for predicting risk for developing breast cancer over the next 5 years from a standard 2D mammogram. The original work behind this algorithm dates back to a publication in 2021 in Science Translational Medicine. This approval was based on training from ~420,000 mammograms from 27 facilities in the US, Europe, and South America. Subsequently, verification data from >122, 000 mammograms 10 US health systems, were presented at the RSNA in December 2025. About 16% of women in their 40s with a normal mammogram were found to be high risk. At the recent RSNA, data are presented taking breast density into account: women in the high-risk AI group had more than a 4-fold higher cancer incidence than women in the average-risk group (5.9% vs. 1.3%). But breast density alone showed only small increases in 5-year risk (3.2% for dense vs. 2.7% for non-dense).

Multiple studies have confirmed the ability to use AI for prediction of future breast cancer, such as one report in over 110,000 women and in a smaller study of more than 13,000 women.

In parallel to CLARITY Breast, there has been extensive work by MIRAI, an academic research model initially developed at Harvard-MIT-Mass General Brigham that has been validating risk and prediction for the next 5 years using AI of the screening mammogram. The work has been extensive in over 21 counties and ~2 million mammograms, in diverse populations. At the December 2005 RSNA annual meeting, prediction of interval cancers was assessed for a cohort of over 130,000 women in the UK. The top 20% of risk accounted for 42.4% of the interval cancers.

While MIRAI is not a commercial product, the algorithm for prediction by DeepHealth (owned by RadNet) and Lunit, referred to above, are in the pipeline for FDA review for their prediction capabilities.

AI detection of high-risk sets the patient up for a tighter surveillance plan that could include MRI or ultrasound, multi-cancer early detection blood tests, or simply more frequent mammography (than every other year) with higher resolution tools such as 3D, digital tomographic synthesis, with an established higher rate of detection than 2D mammography. Identification of high-risk could also lead to a workup for genetic predisposition such as BRCA or other pathogenic mutations that were not previously assessed. When positive, that could also initiate a cascade of checking family members for such mutations.

Share

3. Risk of Heart Disease

The leading cause of death in women in heart disease, not cancer. The diagnosis of heart disease is all too often missed in women for various reasons including clinician bias and atypical symptoms.

Breast arterial calcification (BAC) as detected by AI, turns out to be an important marker for risk of cardiovascular events which affords mammography offer a 2-fer, a form of opportunistic AI imaging. In 2023, the FDA gave clearance to CureMetrix cmAngio for AI detection of breast arterial calcification. That was based on a study on over 10,000 women tracking breast arterial calcification over 4-5 years, and found that an increased in category from mild to moderate) was linked to a 59% higher risk of major adverse cardiovascular events , and for moderate increased to severe BAC a 91% increase. A new appearance of BAC from negative was associated with a 41% increase MACE risk.

Other studies have assessed prediction of heart disease in over 49,000 women followed 9 years using a deep learning algorithm with some predictive accuracy.

In another cohort of more than 5,000 women followed for 6.5 years, BAC was linked to a 51% increased risk of cardiovascular disease events. That was the basis for FDA clearance of Mammo+Heart (below Figure is the summary of data from the study)

Some health systems are currently providing BAC data with for a mammogram for free while others charge $90-$120 for Mammo+Heart or up to $75 for CureMetrix. Other companies are working on FDA clearance for BAC, including DeepHealth

The Obstacles and Limitations

Getting an AI read out from a screening mammogram in the United States is restricted to RadNet, a very large network of over 400 locations, the largest radiology outpatient imaging service in the country. But it only operates in 8 states. And their readout adds cost to the patient that is currently $40 out-of-pocket. CLARITY Breast is now getting rolled out in the US but it also has an extra fee attached for its software interpretation of 5-year risk. And you’ve seen how the breast artery calcification also adds more to the cost. These are unacceptable added costs to patients to get the most information from their mammogram. I’ll come back to this below.

There are numerous algorithms for the initial screening but the only one that has been validated in MASAI is Transpara, which is also being used in ongoing large randomized trials in Norway and the US. RadNet uses DeepHealth, Hungary used Kheiron, Germany used Vara, and a center in Sweden used Linut, all of which have not had the same rigorous assessment. It is possible that there are differences in the performance of these algorithms which would not replicate the findings from MASAI, or, alternatively, could surpass its performance. All these algorithms are being refined, too, such as Transpara tested in MASAI, has been substantially tweaked.

The fact that there are ongoing large randomized trials in Norway and in the US to assess mammography either AI support would suggest this matter is unresolved, that we remain in equipoise. One could argue that such trials may no longer be needed, that the overall proof of benefit is clear, that enrolling participants in a control group without AI support might even be considered unethical. But given current implementation issues in the US with very limited access, added out-of-pocket costs, and lack of insurance coverage, the counter to this would be we’re not ready now to change medical practice anyway. Another point put forth is that survival has not been shown to be improved from mammography AI, but it is not hard to connect the dots from the MASAI data on interval cancers. Note there are few randomized trials with over 100,000 participants and major health outcomes.

For CLARITY Breast and other 5-year predictive algorithms, a concern is that there is no standard protocol for what to do when high-risk is identified and lack of proof that the information changes outcomes.

The conclusion from the recent MASAI paper was: “Further analyses of subsequent screening rounds and cost-effectiveness will clarify the long-term balance of benefits and harms and could provide a strong rationale for implementing AI in population-based mammography screening programmes, particularly in the context of workforce shortages.” This is similar to the vast majority of publications that say in the last line that more research is needed, not making a definitive statement.

The models that led to currently approved or cleared mammography AI tools are all derived without generative AI. Given the power of transformer architecture and foundation models, we can expect to see new AI tools that do all 3 tasks above—detect cancer, prevent cancer, and assess risk of heart disease—in one package. That could make all of this even more accurate, faster and cheaper.

When Is It Time to Change Medical Practice?

Let’s go back to my provocative title of this piece, where I assert all mammograms should incorporate AI. In the US, over 40 million mammograms are performed yearly. The whole rationale for mass screening is early detection. Think of the NCI estimate that 20% of US mammograms read out by radiologists miss cancer. In the US we rely on a single reader unlike European countries that use 2 radiologists.

We now have proof that AI support achieves superiority for the early detection goal, but more than that. It is better (~30% enhanced cancer detection) and faster, saving substantial workload on the part of radiologists. Put that in context to the severe and growing shortage of radiologists. It should be cheaper if the software were embedded in the mammography readout without any additional cost to the patient. If used at scale, a small fee of let’s say $1 could be paid to the company providing the AI. Moreover, the cost of treating Stage 3 breast cancer is between $160,000 to $200,000 in the first 2 years so any early diagnosis at Stage 1 or 2, or even better high-risk , could lead to marked savings in cost.

Mammography with AI support has emerged as the most rigorously studied of all possible indications. It is a standout for demonstrating superhuman performance—“digital eyes”— that see things which humans can’t. I believe the data we now have is compelling and should set the stage for a new standard of care. As I’ve reviewed, there are multiple obstacles that are holding us back, but it all goes back to why aren’t we providing all women with the best information available on their risk, early detection, and potential prevention of breast cancer and, no less, that of heart disease? If not now, then when?

NB: No AI was used in any way to write this post. I have nothing to do, no COI, with any company working in mammography AI.

********************************************************************

Thanks to Ground Truths subscribers (approaching 200,000) from every US state and 210 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Subscribe now

Dr. Kevin Tracey, who directs the Feinstein Institute at Northwell Health, has been studying the vagus nerve for more than 3 decades. In the early 1990’s he made the seminal observation that stimulating the vagus reduces the inflammatory cytokine known as tumor necrosis factor (TNF), what he described at the time as a “holy shit” moment. In 2025 he published the book THE GREAT NERVE with many rich patient anecdotes and the history for how this field developed.

I wrote about the brain-immune axis previously on Ground Truths, spotlighting the vagus nerve’s role. That included much more on depth of the pathways if you are interested.

We discussed the recent FDA July approval for refractory rheumatoid arthritis (RA)(unresponsive to medications or intolerance to medical therapy) based on a sham-controlled randomized trial published in December 2025 in Nature Medicine. It is striking that the benefits were derived from 1 minute of vagal stimulation per day. That stimulation is barely perceived (tingling, many not at all) by device recipients. The surgery takes one hour to implant the tiny stimulator device along side the vagus nerve in the neck.

But this is much bigger than a treatment for RA. It is now being tested for lupus, Crohn’s disease, and other autoimmune conditions. That’s beyond the role vagus nerve stimulation (VNS) has played for epilepsy and depression, independent of VNS’s anti-inflammatory impact (Tracey named it “the inflammatory reflex”).

We also discussed handheld VNS devices, potential use for Long Covid and POTS, cold plunges, heart rate variability, stress, and other topics related to the vagus nerve and parasympathetic nervous system (the brakes, “rest and digest” as opposed to the sympathetic nervous system (the gas, “fight or flight”).

Most people are not aware of this device approved treatment for an autoimmune disease. Our treatments are so drug-centric but they are immunosuppressive, have important side-effects, and are expensive. It’s good to see a non-drug approach get compelling data as an alternative. Moreover, as I recently wrote about, there’s a shift ongoing from treatment to cures vs autoimmune diseases that will be adding to the mix.

Share

Here are some very recent papers about the vagus nerve to give you a sense about how its prominence is getting appreciated more all the time

Gut-brain-vagus axis for reward circuit and addiction, 30 Jan 2026, Science Advances

Randomized trial of VNS for depression , Int J of Neuropsychopharm 2026

The vagus nerve role in heart function after a heart attack, Cell, February 2026

Vagus receptors and hemorrhage, blood volume, Nature, 28 Jan 2026

A Quick Poll

Thank you , , , , , and over 600 others for tuning into my live video with ! Join me for my next live video with Feb 4th, 12:30 PM PT in the app.

**********************************************

Thanks to Ground Truths subscribers (approaching 200,000) from every US state and 210 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

Subscribe now

A Fourth Natural Experiment: Canada

Today in Lancet Neurology, another Shingles vaccine natural experiment was reported that had unique features to help establish cause-and-effect for the vaccine (Zostavax, the live attenuated virus vaccine) and reduction of dementia. To be clear, a natural experiment is an observational study that is based on a naturally occurring situation or policy, such as a country’s policy for vaccine eligibility by birthdate. In many ways, these experiments can be considered better than randomized trials because there are no or minimal selection criteria, they are typically orders of magnitude larger with respect to number of individuals assessed, and they are real world rather than in context of a clinical trial which is subject to the— “Hawthorne effect’”—just being part of a study can have an impact.

In the new study of Canadians, the focus was on over 464,000 people aged 70 years and older who were enrolled in a primary care network; and the more than 250,000 from that group who were born in Ontario. The vaccine eligibility cutoff of birthdate before and after Jan 1, 1946 broke the groups from Ontario into two, for either being or not being vaccinated. With 5.5 years of follow-up, there was an absolute 2.0 per cent point reduction of dementia. Using a second date-of-birth eligibility (Jan 1, 1945) in Ontario, the findings were replicated. Using the same birth cohorts for Ontario compared with the other Canadian provinces that did not implement a Shingles vaccine program, as shown below, the differences for dementia reduction irons ere pronounced, increasing over the length of follow-up. This ability to triangulate by birthdates and to other parts of the country without a vaccine program is unique among the 4 natural experiments and helps to further support a cause-and-effect relationship.

Context With All Four Natural Experiments

Previously, there were natural experiments published for the country of Wales by Eyting et al (N=280,000), Australia by Pomirchy and colleagues (N-101,219), and a US comparison of the live attenuated vs recombinant (Shingrix) vaccine by Taquet et al (N=103,615). The numbers in parentheses refer to the number of people assessed, each analysis enabled by birthdate cutoffs. The reports from Wales, Australia and Canada all used the Zostavax (old) Shingles vaccine whereas the US study assessed the difference between recombinant Shingrix vs Zostavax with the main finding of a 17% increase in dementia-free time. All 4 of the reports included an in-depth analysis of potential confounders, showing, as you would expect, minimal differences between groups vaccinated or unvaccinated.

In the simplified Figure below, I’ve highlighted the consistent reduction in new dementia diagnosis during extended follow-up, along with the differences by sex with 3 of the 4 studies showing significantly greater impact in women. Notably, 3 of these publications were spearheaded by Pascal Geldsetzer at Stanford University.

A recent paper in Cell added another feature about the Shingles vaccine (Zostavax) drawn for the natural experiments. The vaccine not only helped prevent or delay mild cognitive impairment but also slowed the disease course among those with dementia, and reduced deaths attributable to dementia.

Share Ground Truths

Shingles Vaccine and Slowing of Biological Aging

In the Journal of Gerontology, Jung Ki Kim and colleagues from the University of Southern California, published a novel study of 3,884 participants, part of the US Health and Retirement study cohort, age 70+ (in 2016) for 7 domains of biology. Half (49.6%) had a Shingles vaccine. The 7 domains were: 1. adaptive immunity (biomarkers of B and T cells and their subtypes); 2. innate immunity (natural killer cells, other white blood cells besides lymphocytes); 3. Inflammation (IL-6, C-reactive protein, and 7 other blood inflammation markers); 4. epigenetic aging (PhenoAge, GrimAge, DundedinPACE); 5. Transcriptomic aging (transcriptomic mortality-risk age); 6. neurodegeneration biomarkers (p-tau181, GFAP, NFL, and Aβ42/40 Ratio; and 7. simple cardiovascular metrics (blood pressure, heart rate). A composite score was also derived for all domains except adaptive immunity. Not all participants had all the domains assessed but the minimum number for an assay domain was about 1,500 participants.

As you can see below, the regression coefficients with 95% confidence intervals (the correlation) for having the shingles vaccine were associated with significantly more inflammation and slower epigenetic aging. Also a higher level of adaptive immunity was linked with the vaccine.

In the Figure below, the relationship of the Shingles vaccine to the domain over time is plotted. The association of slowing of aging, both by epigenetic clocks and the transcriptomics clock, was somewhat more pronounced (not statistically significant) in the first 3 years of time, but was durable beyond 4 years after vaccination. Innate immunity and inflammation were only observed to be significantly educed beyond 4+ years after vaccination. Notably, there were no effects on the neurodegenerative blood biomarkers markers of p-tau181, GFAP, NfL, and Aβ42/40 ratio) even though there 4 natural experiments showing a reduction of dementia tied to the vaccine.

All of the above data were adjusted for demographic, socioeconomic, and health-related factors.

One Other Thing

The South Korea Study and Cardiovascular Protection

In May 2025, there was a nationwide report of over 1.6 million South Koreans who either got or did not receive the Zostavax vaccine. While not a natural experiment, using matching and propensity analysis, and adjustment of known confounding factors, an impressive improvement of cardiovascular outcomes across the board was seen, as summarized in the graph below (MACE-major adverse cardiovascular event, especially in men and age 60+. These results replicate other studies of the Shingles vaccine for cardiovascular protection, at a large scale, although not established via natural experiments.

Share

The Bottom Line

The case for the Shingles vaccine linked to reduced dementia, which is mostly less Alzheimer’s disease, has been strengthened with a 4th natural experiment that not only corroborates the previous ones, but also, via data triangulation, helps support a cause-and-effect. The concern with interpreting these studies has been whether people who get the Shingles vaccine are selecting out a special group, a biased sample, if you will. Beyond the inherent strengths of a natural experiment at scale, comparing data to the rest of the country without a vaccination program adds another dimension towards certainty of the effect.

But there are uncertainties. Why do women have more benefit in 3 of the 4 studies, and in the largest (Wales) there was no benefit seen for men? We know that Alzheimer’s disease is more frequent in women, but that doesn’t explain the disproportionate benefit. We now have some data to go from via the mechanistic, biological aging study, with 3 observations, as seen the Figure above: (1) the slowing of epigenetic and transcriptomic age was greater in women; (2) there were significant differences for the vaccine correlation with reduced levels of innate and adaptive immunity, compared with men; and (3) the change in neurodegenerative markers were linked with women, not men. These at least provide some hints for why women are driving more benefit.

Still unknown is whether the vaccine has a direct effect on the herpes zoster virus or is working indirectly to reduce inflammation and modulate the immune system. We now have evidence for the latter, but that doesn’t rule out some connection with the virus.

We also do not know whether people getting the vaccine below age 50 (current US policy is 50+) derive more or any benefit, and whether the association holds for people who have had Shingles.

As reviewed in the prior Ground Truths, the protection against dementia was predominantly vs Alzheimer’s disease in the studies that got into subtypes of dementia. If this vaccine was a drug and reduced Alzheimer’s by 20%, it would be considered a major breakthrough for helping to prevent the disease! But as a vaccine it hasn’t reached any sense of being a blockbuster; this indication was never envisioned when the vaccines were developed and we only “backed into it” from these large and highly consistent natural experiments.

The study in the US is the only one that factored in the new recombinant Shingrix vaccine compared to the old live-attenuated virus version. It is much more effective than Zostavax for preventing Shingles (~50% vs >90% protection) and the Taquet report also showed it linked to 17% more from freedom of dementia-diagnosis time. That would suggest we may be underestimating the reduction of Alzheimer’s from the 3 natural experiments that used an outdated vaccine.

If you are 50+ and have not gotten Shingrix vaccinated, you may want to consider that. You get protection vs Shingles (which can be dreadful), slowing of your biological aging (by methylation and RNA metrics), and ~20% reduction of dementia, predominantly related to Alzheimer’s disease. All of this benefit is magnified in women compared with men, but 3 of the studies showed some reduction of dementia in men. As a tradeoff, men appear to derive more cardiovascular benefit, but that evidence is not as compelling as protection from dementia from natural experiments.

Finally, we always want to have independent replication for studies; that’s especially vital when an important finding was not hypothesized or anticipated. Now we have 3 replications and an extension from the original natural experiment. That’s pretty convincing. Beyond that, in correspondence with Prof Pascal Geldsetzer of Stanford (if you check the publication links, he’s senior author on many of them), I learned there are at least 3 more country natural experiment replications on the way for the Shingles vaccine and reduction of dementia. But we need more mechanistic studies for how the benefit is achieved, but the new one this week is a good start! If we can nail down the mechanism, it may have an impact on developing other preventive strategies.

NB: No AI was used in any way to write or research this post. I have nothing to do, no COI, with any company making a vaccine or drug.

********************************************************************

Thanks to Ground Truths subscribers (approaching 200,000) from every US state and 210 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Back in 2005 Dan Buettner patented Blue Zones. He’s written 9 books, of which 5 were NY Times bestsellers, and has another one in the works. His 2023 Netflix documentary series “Live to 100: Secrets of the Blue Zones” won Emmy awards and was widely viewed. Many of the main points that Dan has emphasized over the years—healthy diet (he highlighted whole grains, beans, nuts, greens, and “peasant food” here), physical activity, social engagement, and sense of purpose—are backed up by randomized trials and/or large, prospective studies, as I reviewed in Super Agers.

In this interview, I asked Dan about the critique he’s faced, predominantly from Saul Newman, a biologist in the UK, about accuracy of the data for extreme longevity in the blue zones. In December 2025, two of his collaborators published in The Gerontologist a rebuttal response (open-access) entitled “The validity of Blue Zones demography: a response to critiques” on the rigorous demographic work they’ve done.

We also discussed the marketing and business operations of Blue Zones LLC, the company he sold to Adventist Health in 2020. His son, Danny, is the EVP of the company and likely successor to Dan’s work in the future. As Dan said, “He’s my genetic upgrade.”

I hope you find this conversation informative. An AI-generated transcript is available in the tab at top right above.

Some biomedical updates from the past week:

1. A vaccine to prevent colon cancer in carriers of mutations of Lynch Syndrome looks good for strong immune response and safety, ready for Phase 3 clinical trials

2. A review of the data of Tylenol during pregnancy reaffirms its safety and lack of increased risk for autism, ADHD, and intellectual disability.

3. Our perspective/review on how AI and large language models can reduce global health inequities

4. Another big jump vs refractory autoimmune diseases, this time for hemolytic anemia, using engineered T cells. See my recent review of this topic, from treatment to cures.

5. A pair of new large prospective cohort studies that reinforce the importance of even small increases in physical activity, along with sleep and diet, for reduction all-cause mortality and improvement in healthspan.

Subscribe now

Thanks to Ground Truths subscribers (nearly 200,000) from every US state and 210 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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026

Thank you , , , , , and many others for tuning into my live video with ! Join me for my next live video in the app.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

In this post, I’ll review the relevant data for low-dose aspirin, including some nuances, the guidelines, longer follow-up, and the question of use for cancer prevention.

Subscribe now

The 3 Pivotal Trials

A summary Table of the wealth of new data from 3 randomized, placebo-controlled mega-trials published in 2018.

ASPREE assessed aspirin in a healthy elderly population (mean age 74) of 19,114 participants from Australia and the United States. There were 1,052 deaths during nearly 5 years of follow-up, with a 14% higher rate of death for aspirin (all-cause mortality) mostly accounted for by increased cancer mortality (3.1% vs 2.3%, a 31% increased hazard ratio). There was no significant reduction of cardiovascular events for aspirin, which was dosed at 100 mg enteric-coated. Aspirin significantly increased major bleeding rates with rates of 8.6 events per 1,000 person-years in the aspirin group versus 6.2 per 1,000 person-years in the placebo group (HR, 1.38; P<0.001), a nearly 40% higher risk, primarily driven by gastrointestinal and intracranial bleeds.

Here is a graphic summary of the major outcomes in ASPREE as I published in SUPER AGERS.

ASCEND was a primary prevention trial in people with diabetes, a key risk factor, but no evident cardiovascular disease. A total of 15,480 participants with mean age of 63 years were followed for 7.4 years. As shown below, the 12% reduction of vascular events was offset by a 29% excess of major bleeding events. The conclusion of the trial report was was follows: “The absolute lower rates of serious vascular events were of similar magnitude to the absolute higher rates of major bleeding, even among participants who had a high vascular risk.”

ARRIVE enrolled 12,546 participants deemed at moderate risk for cardiovascular disease, age 55+ for men, 60+ for women, and followed for 5 years and found no benefit for reduction of enteric-coated aspirin time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischemic attack (shown below). There was about a doubling of gastrointestinal bleeding events.

Long-Term Follow-Up of ASPREE

The ASPREE trial was most relevant for extrapolating to healthy people of advanced age, without diabetes. Fortunately, there was extended follow-up for 15,668 participants another 4.3 years after the primary report. This revealed a 17% increase in major adverse cardiovascular events and 8% increased of major bleeding events for the low dose aspirin group vs placebo, respectively. The cumulative results for the full extent of follow-up are shown below. MACE is major adverse cardiovascular event.

Share Ground Truths

Revised Guidelines

These trials led to the ACC/AHA and the US Preventive Services Task Force (USPSTF) to change their recommendations for low-dose aspirin.

Here are the ACC/AHA guidelines summarized:

And the USPSTF guidelines:

You can see the contraindication for use of low-dose aspirin by both guidelines, with a cutoff of age 70+ for ACC/AHA and age 60+ by USPSTF. The lower age for the latter was backed up extensively by updated modeling in 2022.

What About Special Risk Factors?

Two risk factors that are frequently asked about are high coronary artery calcium scores by CT (CAC) and high blood levels of LP(a). There are no data to support primary prevention of low-dose aspirin for elevated Lp(a) in people of advanced age, although this is a recognized risk factor for atherothrombotic events.

The ACC/AHA guidelines addressed high calcium scores from the MESA cohort results: elevated CAC score can be used to reclassify risk and guide the personalized allocation of aspirin for adults aged 40 to 70, but there is no indication for use for age 70+. In the MESA cohort, not a randomized trial, the numbers needed to treat for CAC of 100 and 400 are shown below over 5 years to prevent 1 event. 400 people are needed to treat for 5 years with a CAC of 400 or higher to prevent 1 event. That is the basis for the ACC/AHA recommendation of low dose aspirin for people age <70 years. It is not nearly as well backed up as the data from the 3 pivotal randomized trials.

Lessons from President Trump

A lengthy interview with President Trump about his health was published in WSJ, reporting that his doctors advised taking 81 mg of aspirin to prevent heart disease but he takes 325 mg. He explained: “They say aspirin is good for thinning out the blood, and I don’t want thick blood pouring through my heart. I want nice, thin blood pouring through my heart. Does that make sense?”

No, it doesn’t make any sense! Aspirin reduces platelet aggregation (clumping); it’s not a blood thiner. Blood thinners are drugs that work on the clotting proteins such as Coumadin or Apixiban (Eliquis). Trump is 78 and shouldn’t be taking aspirin at any dose for primary prevention, even with an elevated CAC of 140 that was reported in 2018. Added to that is his unwillingness to accept his physician recommendations, which are not evidence-based and that too is concerning.

Share

Cancer Prevention

There has been a longstanding debate about whether low-dose aspirin should be used to prevent cancer, especially of the colon. in older adults. The ASPREE trial of healthy aged participants helped to understand the benefit of aspirin for primary prevention of cancer. Recall that the trial found higher cancer-related mortality, which is certainly not favorable. But best estimates showed 100 mg aspirin provided some modest protection from developing cancer (Figure).

Of note, that benefit was linked to having clonal hematopoiesis of indeterminate origin (CHIP, blood stem cell clones), with a variant allele fraction (VAF) of 10% or higher, a frequent finding in people of advanced age (>10% by age 70), but one that we do not assay in medical practice! As I previously reviewed, CHIP increase is linked with the risk of blood and other cancers, and cardiovascular events.

That needs to be assessed prospectively, but there may well be a group of healthy elderly who would benefit from low-dose aspirin if we assayed CHIP or other biomarkers of high-risk for cancer.

Concluding Remarks

The body of evidence reviewed here strongly argues against use of low-dose aspirin for people of older age (be it 60+ or 70+) for primary prevention—without heart disease. Without cardiovascular disease means no prior heart attack, bypass surgery, or percutaneous coronary intervention (i.e. stent) since these represent secondary prevention, which has clearcut net benefit for aspirin. That benefit extends for secondary prevention of cerebrovascular disease (TIA, stroke) individualized for the basis of risk of major bleeding.

Beyond the review of the data, it is notable that 7 years after these pivotal trials were published, the medical community is not fully aware of the data. As mentioned in the opening paragraph, the latest available data suggests 1 of 3 healthy Americans age 70+ are still taking low-dose aspirin for primary prevention, as suggested by their physicians. There’s a much lesser percentage taking aspirin by their own choice. (Figure).

The recent article about President Trump’s aspirin self-dosing has helped to put the aspirin story back into the spotlight. I hope this edition of Ground Truths helps get the proper evidence out there. It is striking to me how hard it is to change the practice of medicine, and how long it takes, even when we have such a solid basis.

Thanks to Ground Truths subscribers (approaching 200,000) from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join!

Subscribe now

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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026

There was an interview with me about what I eat and what I avoid in the Washington Post today. If you’re interested here is a gift link.

It was great to see that SUPER AGERS was selected by a big non-fiction book club readers as the second favorite book for 202

I made this infographic with the help of Notebook LM to summarize many of the concepts we discussed. (Notebook LM is free and worth trying)

Subscribe now

We went over his new review with 24 co-author leading experts in the recent issue of Neuron

A Clever Cover

The drainage system anatomy on influx and efflux (blue arrows)

The 3 ways the flow of glymphatics are modulated. I mentioned the recent studies that show atrial fibrillation, via reduced cardiac pulsation, has an effect on reducing glymphatic flow.

Share Ground Truths

We also discussed his recent review on the immune surveillance system in Cell:

A schematic of key channels for the “faucet” and “drain”

and how the system changes from healthy to central nervous system autoimmune diseases (such as multiple sclerosis) and aging with different immune bar codes.

The outsized role of astrocytes in the brain, a subject of recent Nature feature, was also mentioned.

Our understanding of the brain’s immune system has been completely revamped. Kipnis’s recent review in Nature Immunology highlights the critical role of the outer layers —the skull, dura and meninges—as an immune reservoir that is ready to detect and react abnormalities in the brain with a continuous “intelligence report.”

Subscribe now

Notably, Kipnis touched on lymphatic-venous anastomosis (LVA) surgery (Figure below) for Alzheimer’s disease which is popular in China, available at 30 centers in multiple cities, and the subject of multiple randomized trials as a treatment for Alzheimer’s. Trials of LVA surgery are also getting started in the United States for treatment of Alzheimer’s and Parkinson’s diseases.

Here is a Figure to show the surgical anastomoses (connections) from the deep cervical lymphatics to external jugular and internal jugular veins

This podcast was packed with insights relevant to health, spanning sleep quality, sleep medications, autoimmune diseases, and Alzheimer’s disease. I hope you find it as informative and engaging as I did.

A Poll

************************************

This is my 4-year anniversary of writing Ground Truths. Post number 250! That’s an average of more than 1 per week, nearly 5 per month. Hard for me to believe.

Thanks to Ground Truths subscribers (approaching 200,000) from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join!

Subscribe now

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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026

Thank you , , , , , and many others for tuning into my live video with ! Join me for my next live video in the app.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app

But there is a remarkable pivot now that has accelerated in 2025 to achieving cures!

I wrote about this in a SUPER AGERS chapter entitled “ Controlling Our Immune System” and this approach is rapidly pushing forward. This edition of Ground Truths will cover: (1) the 2 major shots on goal for curing autoimmune diseases, and (2) how all the progress in immunotherapy for cancer is laying the foundation.

Subscribe now

Let’s first run through the 2 major potential routes to cure.

The Hard Reset: Engineered T Cells, known as Chimeric Antigen Receptor (CAR)

CAR T cells have been used for cancer with marked success for certain types of blood “liquid” cancers, but much less efficacy in solid tumors, an area of extensive ongoing research. In 2021 in Germany , a single infusion of CAR T cells targeting CD-19 led to the first cure of a 20-year-old woman with severe, refractory systemic lupus erythematosus (SLE). This was a dramatic case report, as exemplified by the Figure below. Look how all these conditions resolved over 6 weeks.

A few years later the same group of German researchers, led by Georg Schett, demonstrated more prolonged remission and cures for patients with lupus, systemic sclerosis and idiopathic inflammatory myositis. Such work has been extended to multiple sclerosis with the CD-19 target or, more recently, with a B cell maturation antigen that extends the target to long-lived plasma cells (and dual targeting CARs vs CD19 and BCMA). The work for CAR T in autoimmune disease has been assessed for many other diseases including myasthenia gravis, stiff person syndrome, ,neuromyelitis optica spectrum disorder, pemphigus vulgaris, rheumatoid arthritis, Sjogern’s disease, and Type 1 (autoimmune) diabetes. Systemic sclerosis has been successfully approached with CAR NK, engineered cells directed against natural killer cells. Some of these diseases have been using other targets besides CD-19, such as CAR-Treg (regulatory T cells that put on the brakes of the immune system, their discovery won the Nobel prize in 2025) for rheumatoid arthritis and type 1 diabetes or an antigen-specific B cell receptor (DSG3-CAART) for pemphigus, a life-threatening skin disease caused by autoantibodies vs desmoglein (Dsg3).

Why is this referred to as a “Hard Reset”? It’s because the B cells are depleted and when they repopulated there’s no longer the self-attacking, disease-causing immune cells. It is as if the new, naive lymphocytes forgot they were previously engaged in warfare, a veritable resetting of the immune system. Like rebooting your computer the was not working and then everything runs fine..

But until 2025 the CAR T field relied on outside the body (ex vivo) engineering of the T cells. That’s laborious, time consuming, with complex manufacturing, very expensive, requiring hospitalization and chemotherapy. It requires all of a person’s lymphocytes to be removed and transferred to a facility where the cell engineering can be done, and a ~3-week delay for the CAR T infusion.

Share

Now everything is moving toward off-the-shelf, universal, inside the body (in vivo), known as allogeneic, from healthy donors or a master cell bank, with the key requirement of a delivery mechanism such as a lentiviral vector or mRNA with lipid nanoparticles (LNP, panel b) or bispecific antibody (panel c below) that pairs up the T and B cell it’s meant to kill. The latter achieved lasting remission with deep B cell depletion in 6 of 10 patients with refractory autoimmune diseases but is transient as compared with the lentivirus vector or mRNA delivery durable approaches. The in vivo, in-the-body strategy avoids the need for lymphocyte depletion that requires chemotherapy with its attendant toxicity. This can be done as an out-patient, preempting a prolonged hospitalization for a patient waiting without lymphocytes, and preserving the patient’s immune system.

This inside the body, off-the-shelf strategy has already been shown to be safe and successful in Phase 1 trials of refractory SLE and in patients with systemic sclerosis or severe myositis. Below is a schematic from a recent report of 5 cases with success for SLE in vivo using mRNA for delivery; HN2301 is an engineered lipid nanoparticle.

Several companies are in clinical trials with in vivo CAR T for autoimmune diseases including Capstan Therapeutics, Kite Therapeutics, Umoja Biopharma, and Shenzhen Magic-RNA. The striking progress in this field towards universal, potential one-shot cures is tempered by residual anticipated high cost, the cytokine release syndrome and neurotoxicity that can occur with CAR T. The mRNA and non-viral vectors are considered a better choice than a lentivirus vector because of the latter’s potential risk of mutagenesis and cancer.

Share Ground Truths

The Soft Reset: Inverse Vaccines to Achieve Tolerance

I wrote about this in a prior Ground Truths on tolerogenic vaccines, the opposite of standard vaccines that boost the immune system. By leveraging the liver, an immune-privileged organ that when processing an antigen target, by attaching with a sugar, the liver can flag it as safe and issue a “do not attack.” Alternatively, tolerance can be achieved via the spleen route by masquerading the target antigen inside lipid nanoparticles. Inverse vaccines are being pursued in celiac disease (Anokion, with positive clinical trial results reported earlier this year) , multiple sclerosis (Anokion, Moderna, BioNTech), and Type 1 diabetes (Diamyd Medical), rheumatoid arthritis (Janssen) clinical trials.

With the help of Nano Banana I made the infographic below to demonstrate the two mechanisms (of many) to achieve tolerance with vaccines. Other non-vaccine, cell therapy routes include use of Tregs (such as via CAR-Tregs) that put the brakes on the immune system or dendritic cells that have been transformed to be tolerogenic. I won’t go into the details here but this recent review paper provides that information, with new methods to produce abundant, long lasting T regs. Notably, the mechanism by which dendritic cells can achieve immune tolerance was just published this week.

The other potential longer term strategy I want to call out is thymus rejuvenation. The thymus glad involutes in adolescence and many autoimmune diseases are age-related. We recently have learned much more about the thymus gland’s biology, evolution, and how given FGF21 can restore function of the involuted thymus. Also, just last week there was a publication on the molecular mechanism for how axolotl, a vertebrate, is able to regenerate its thymus gland from scratch after it has been removed. All of this could be useful for either prevention or potential cure of some autoimmune diseases in the future.

How Progress in Cancer Fuels Autoimmune Disease Innovation

Cancer biology is the mirror image of autoimmunity. Predisposition to cancer occurs when the immune system is hypoactive, losing its protection, whereas autoimmune disease reflects hyperactivity and a dysregulated state. The approach to these 2 different diseases is like a rheostat, dialing the immune system up for cancer or down for autoimmune disease. The B cells are a common culprit, hence the successful use of CAR T vs B cells for both diseases. The checkpoint inhibitor PD-1 (prototype Keytruda) is to cancer (cut the brakes on the immune system) as PD-1 agonists (slam on the brakes) are to autoimmune diseases. Similarly, cancer vaccines to rev up immunotherapy are the opposite of inverse, tolerogenic vaccines as reviewed above. CRISPR genome T cell editing could amp up T cell killing function for cancer or make them into T-reg peacekeepers to stop autoimmune attacks. This review paper and its Figure below demonstrates the reciprocal relationship between CAR T for cancer and autoimmunity. What is important to emphasize is all the work to achieve in vivo, universal CAR T works for both diseases. Anything that helps cancer immunotherapy has the big dividend of also helping the efforts for curing autoimmune diseases. The new field of structural immunotherapeutics has legs to achieve precise control of our immune system vs either sets of diseases.

I’ve been impressed with the output from Gemini-3 Nano Banana for making science infographics, so I made this one for the mirror images of these 2 diseases.

Subscribe now

Concluding Remarks

I hope I am able to adequately convey the excitement in this field. This represents one of the biggest shifts in a domain of medicine that we’ve seen in decades. It has been stunning to see for the first time one-shot cures in patients who were refractory to all approved treatments. There’s a paucity of true cures in medicine. Considering that 1 in 10 people have an autoimmune disease, and these conditions have never garnered the level of attention as cancer, cardiovascular, or neurodegenerative diseases, these big steps of progress are especially welcome. Mirror biology and goals of all the clinical work in cancer directly benefits autoimmune diseases, turbocharging this movement.

It’s still early, but most major autoimmune diseases are getting approached by both engineered cells and inverse, tolerogenic vaccines. The off-the-shelf, universal engineered cell approach is ahead of the inverse vaccines so far, and the refinements in the works are extensive, as shown in the Figure below. Eventually, both major routes of cell therapy and tolerogenicity are very likely to pan out and we should see a big dent in autoimmune diseases in the future. Of course, for any scaling, this will require availability at low cost, limiting side effects, making in practical and accessibility to all, avoiding inequities. But given all the rapid progress I’m confident we’ll get there in the years ahead. We’e seeing the initial stages of a renaissance vs autoimmunity. Curing instead of just treating autoimmune diseases.

Last week, I did the Big Interview at WIRED on the science of super agers and extension of our healthspan. You can view it here, with transcript

Also on a related immune system disorder, Long Covid, this week we finished enrollment for the 1,000 participants randomized to tirzepatide vs placebo, the first large RCT for this debilitating condition affecting millions of people with no known validated treatment.

I’ll be interviewing Dan Buettner on Blue Zones tomorrow, 15 Dec, live on Ground Truths at 12:30 PM. And later this week 17 Dec, with Dr. Jonathan Kipnis on getting toxic waste products out of our brain. Join us via the app. *****************************

Thanks to >190,000 Ground Truths subscribers from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile.

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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026

A recording from my enthralling conversation with Prof Matthew Cobb about the life and science contributions of Francis Crick, regarded as one of the most influential biologists of all times, along with Darwin and Mendel. As you’ll see, there’s so much more to Crick’s story than cracking DNA’s double helix structure in a matter of weeks with James Watson. Matthew Cobb, Emeritus Professor of the University of Manchester, has written several award-winning books on life science, but I think this is his most important one to date, deeply researched and a thrilling account of Crick’s life, clearing up, as best as one can, many questions, and presenting some surprises.

Subscribe now

The transcript is available (A.I. generated) by clicking at the top right.

A few things we discussed

—Crick’s reaction to James Watson’s book

Crick contrasted his own approach to science writing with Watson’s memoir: “The difference between my lecture and your book is that my lecture had a lot more intellectual content and nothing like so much gossip. (...) Your book on the other hand, is mainly gossip and I think it a pity in this way that there is so much of it that it obscures some of the important conclusions which can be drawn of what we did at the time”.

—The Peyote Poem, by Michael McClure (part 1) that had a big influence on Crick

—Crick’s 1994 neuroscience book “The Astonishing Hypothesis”

“You, your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free Weill, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules.”—Crick

The book has been reviewed at Science, Nature, The Economist and many other journals. Here is a gift link to The Economist It has deservedly been named a best book of 2025 by The Guardian, The Economist, and many other media.

Thank you , , , , , and over 500 others for tuning into my live video with !

*********************

Upcoming, this Wednesday 9AM PT, live podcast

I will be interviewing founder of the Blue Zones

Join us!

**********************

Thanks to US News for recently being named one of the 25 best leaders in the United States

https://www.usnews.com/news/leaders/articles/best-leaders-2025-eric-topol

^^^^^^^^^^^^^^^^^^^^^^

Thanks to >190,000 Ground Truths subscribers from every US state and 210 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile.

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. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

Get more from Eric Topol in the Substack app

Available for iOS and Android

Get the app