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?

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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!

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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)

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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!

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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

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.

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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.

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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.

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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.

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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. *****************************

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Early Thoughts on Heart Attack Elimination

The dream of eradicating heart attacks was articulated in 1996 in a Science editorial entitled: ”Heart Attacks: Gone with the Century?” It was written by Michael Brown and Joseph Goldstein, awarded the Nobel Prize in 1985 for their groundbreaking cholesterol metabolism work that led to statins. Although statins have helped reduce the risk of heart attack, we still have over 800,000 each year in the United States, which is similar to the data spanning 2012 to 2022, and heart disease remains the number 1 killer despite a marked reduction in death rates over the past 2 decades. Even with 1 in 4 Americans taking statins now, it’s clear we’re far away from their disappearance. One prescient note in the Science editorial was “The challenge is to develop noninvasive screening methods to detect coronary atherosclerosis in its earliest stages.”

We’ve long known that it takes decades for atherosclerotic plaque to develop, as visualized to be prevalent (albeit not obstructive, i.e severe narrowing, blood flow-liming) at significant frequency in teenagers and young adults (Figure). Yes, it’s an age-related disease, but it typically starts very young.

Finding the Vulnerable Plaque

The pathology studies from post-mortem studies have provided clearcut features of arteries in heart attack victims. Chief among them is the thin fibrous cap of the atheroma (TCFA) plaque (Figure) which leaves it prone to erosion, cracking or rupture, the immediate event (usually accompanied by a blood clot) that precedes a heart attack. A lipid-rich necrotic plaque (dead cells, cellular debris, cholesterol and other lipids) is typically underneath the thin cap, and inside the plaque there is inflammation with accumulation of macrophages and T cells. Unlike stable plaque, the vulnerable plaque does not contain dense calcification. (This one of the reasons I have never ordered a CT calcium score for any patient since they are often highly misleading). The minimal lumen area (MLA, channel for blood) is reduced. The artery can enlarge outwardly, known as positive remodeling, to compensate for accumulation of plaque.

But until there were ways to image inside the coronary artery, we relied on angiograms, a 2-dimensional silhouette of the lumen—the channel through which the blood flows. The 1995 paper I co-authored entitled “Our Preoccupation With Coronary Luminology” reviewed the serious problems and limitations of relying on angiograms. That was near the time when intracoronary imaging was receiving increasing attention for illuminating what was going on inside the artery wall, not just in the lumen. Both intravascular ultrasound (IVUS, middle images below) and optical coherence tomography (OCT) (left images below) provide exquisite images from within the artery, that is they require a catheter to be inserted into the artery being assessed, thus considered a form of invasive imaging.

From intracoronary imaging we learned the natural history of atheroma progression. As seen below from a prospective study of nearly 700 patients, subsequent major cardiovascular events during 3.4 years of follow-up were mostly in atheroma that were mild by angiogram (non-obstructive) but by IVUS had thin-cap fibroatheroma (TCFA), high plaque burden (PB) or small luminal area (MLA). Features that would not be picked up by an angiogram.

So now that we could identify these high-risk atheroma—vulnerable plaques—there was thought they might be stabilized or “sealed” with ballon angioplasty. Bernhard Meier advanced this idea, as did an insightful perspective by Kern and Meier.

That concept hung is suspension, unproven, for a number of years until a recent randomized trial was conducted in South Korea, Japan, Taiwan and New Zealand of plaque sealing known as PREVENT, demonstrating for the first time that intervention of vulnerable plaque (determined by IVUS) with optimal medical therapy led to reduced major events compared with optimal medical therapy alone (Figure). The study concluded “These findings support an expansion of the indications for percutaneous coronary intervention to include non-flow-limiting, high-risk, vulnerable plaques.”

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New Thinking

In June 2024, here at Ground Truths, I wrote about the Big Miss: Inflammation and Cardiovascular Disease emphasizing the need to detect arterial inflammation and acknowledge the importance, redirecting our attention to non-obstructive coronary disease. In April 2025, The Lancet Commission, Rethinking Coronary Artery Disease: moving from ischemia to atheroma” highlighted the opportunity to save 8.7 million lives per year globally by focusing on early detection of atheroma (Cover of that issue below).

More recently, in September 2025, the American College of Cardiology published a scientific statement on inflammation and cardiovascular disease. A key conclusion:

“The time is also ripe for the development of strategies to promote increased physician awareness of the crucial role of inflammation in CVD and accelerate the adoption of evidence-based, guideline-directed anti-inflammatory therapy through dissemination and implementation research.”

Taken together, these recent papers are indicative of the shift of thinking and embracement of the need to detect vulnerable, inflamed, high-risk plaque if we are going to make further progress for avoiding heart attacks and cardiovascular deaths.

Non-Invasive Coronary Imaging With A.I.

Detection of the high-risk atheroma has been made possible without a catheter placed into the artery using CT imaging with an injection of contrast dye (angiography), known as CCTA (for coronary computed tomography angiography) There are 4 companies that have used A.I. of the images obtained to identify high-risk, non-obstructive plaque. I’ve made this Table below to summarize what each company does, since they are quite different. CLEERLY, which as a tag line on its website “Creating A World Without Heart Attacks,” detects plaque features with the ground truths (reference markers) shown below, and has a clinical validation study to link their detection to events. ELUCID focuses on plaque composition, using histology as the reference marker, but has no clinical event validation. HEARTFLOW uses fluid dynamics and 3D plaque reconstruction and has published a paper for clinical event validation. CARISTO, which is pending but not yet FDA-cleared (the other 3 are), uses the fat attenuation index (FAI), the peri-vascular fat tissue when by histologic study to be rich indicative of inflammation and rich in T cells (see also Top Figure of this post). This is the only technology that has thus far been linked to cardiac mortality.

Below are data from 40,000 consecutive patients with CCTA in 8 centers in the UK with up to 10 year follow-up using the CARISTO FAI. Even 1 inflamed artery raised the risk of death 13-fold compared with no inflamed arteries! Take a look a the paper for data partitioning obstructive and non-obstructive lesions, inflamed or non-inflamed.

Last week it was announced that Medicare will reimburse for the FDA-cleared non-invasive coronary imaging A.I. companies more than $1,000 per scan. Another sign of a big shift.

New Drugs

Besides the new non-invasive image algorithms, last week’s American Heart Association presentations were noteworthy for many new drugs emerging for treating abnormal lipids and preventing progression of atherosclerosis. This Wall Street Journal article below provided a useful summary. The toolkit is rapidly expanding with the anticipated introduction of potent oral PCSK9 blockers, Lp(a) inhibitors, more ANGPTL3 blockers, along with anti-inflammatory drugs such as different interleukin blockers and the possibility of using GLP-1 drugs for this purpose. GLP-1 drugs have already been shown to reduce heart attacks in people with obesity and we recently learned that only about a third of the benefit was weight-loss dependent.

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Preventing Coronary Artery Disease Events

We’ve gone from the miscue of statins ending heart attacks to now A.I. purportedly “creating a world without heart attacks.” The problem, once again (besides exuberance), is that there is far too much fixation on just the atheroma, the vulnerable plaque, instead of on the high-risk patient. We have far better ways to identify vulnerable patients and we’re not doing it. I wrote extensively in SUPER AGERS about the many missed opportunities to do this, such as polygenic risk scores (PRS) for coronary artery disease. They are the most extensively validated of all PRS common diseases, available from more than 10 companies, getting initial uptake in some health systems, but have not reached general use. The value of PRS for assessing risk is independent of family history or risk factors of diabetes, smoking, hypertension, high cholesterol, sedentary behavior, or obesity. We don’t generally measure blood inflammation markers such as high-sensitivity C-reactive protein, and have no assay for clonal hematopoiesis of indeterminate potential (CHIP) even though they CHIP is clearly linked with risk of cardiovascular disease. The protein organ clocks that quantify the pace of aging a person’s arteries and heart are prime candidates to add to the way of finding high-risk individuals. A retina photo or OCT, easy and inexpensive to obtain during an eye exam, can be used with A.I. interpretation to detect subclinical coronary artery atherosclerosis (figure below), or predict heart attacks. The latter report concluded: “Our results indicate that one could identify patients at high risk of future myocardial infarction from retinal imaging available in every optician and eye clinic.” Importantly, each layer of data about heart risk can be corroborated and integrated with the other layers.

In a recent Ground Truths I reviewed the Delphi2m large health model which predicted over 1,200 diseases and health events at the individual level for the next 20 years, not just what events but when. That was just from the electronic health record without the other layers of data I allude to here, and with a GPT-2 model with very low parameters compared to current models.

The accurate and comprehensive identification of high-risk individuals needs to be inexpensive, so it can be applied globally. The cost of obtaining and interpreting a person’s data for their genomics, proteins, biomarkers and eye grounds could be extremely low.

Concluding Remarks

I do think there is a highly promising way forward to markedly reduce heart attacks. Even with new reimbursement, we cannot do CCTA and A.I. in most people, no less on a serial basis. But by accurately determining who are the individuals at high-risk—with multiple layers of data— genes, proteins, inflammation markers, imaging—the way to get ahead of their progression of atherosclerotic disease has never been more impressive. And an expansive array of drugs adds to the mix. Medications not just to address high LDL cholesterol but also Lp(a), for which we’ve never had a drug, and ways to suppress arterial inflammation that is not just mediated by abnormal lipids. While we’ve recently seen a big shift in thinking, we have no indication of any shift in action. That’s highly warranted. That’s what we need.

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A Brief Background

Over the past two decades there have been many reports that multilingual individuals have improved cognition compared with their monolingual counterparts with better attention, task switching, working memory and potential protection from Alzheimer’s disease. It’s not just advantages for functionality. Brain structure studies in multilingual vs monolingual participants have shown increased gray matter density in key regions (caudate nucleus, left inferior parietal cortex) that are linked to executive function, such as this frequently cited 2004 paper (Figure below). This feature is known as neuroplasticity—the brain’s ability to change and reorganize its neural connections throughout life. Note how the gray matter density increase is maximum when proficiency in a second language occurs as a younger age.

Most of the studies of multilingualism’s benefits have been small, with confounders, and mainly focused on the brain and cognitive function. Today, the new report in Nature Aging provides a far more comprehensive picture. In this edition of Ground Truths, I’ll review the paper, its limitations, and where we go from here.

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The Paper

Agustin Ibañez, from the Global Brain Health Institute and Scientific Director of the Latin American Brain Health Institute, along with colleagues throughout Europe, published a study of over 86,000 adults from age 51 to 90, mean age 66.6, from 27 countries in Europe. They developed a biobehavioral age gap (BAG), like body-wide or organ clocks, that are a metric of the pace of aging of an individual or organ, from all the known risk and protective factors, some of which are shown below. Multi- or mono-lingualism was derived from country level data. Individuals underwent repeat national surveys for all the known protective and risk factors on a longitudinal basis. The survey questions are published in the Supplementary data.

There were 3 major analyses, one by cross-section (aggregate data for multi vs mono-lingual), longitudinal data that factor in time of follow-up, and a subgroup analysis by age. In the cross-sectional analysis, monolinguals were 2.1 fold more likely to develop accelerated aging whereas those speaking one or more languages were 2.2 time less likely (odds ratio of 0.46) to experience accelerated aging. For the longitudinal analysis, the risk ratio for monolinguals was 1.4 fold for accelerated aging, and 1.4 fold less for multilingual. You can see the dose response with increased additional languages and more protection, i.e. less likely for developing accelerated aging. Correspondingly, the age subgroups for the cross-sectional (top) and longitudinal (bottom) of the graph at bottom below shows the risk or protection to be present across all ages, increasing risk of accelerated aging in monolinguals with increasing age. In contrast, the multilinguals with 2 or more additional languages had more protection within older age groups (data not shown below, in Extended Figure 1 of paper).

The compelling part of the report s the depth of analysis and stress testing of their results. They controlled for everything possible (education, cognitive function, physical activity, etc), including all different types of exposures (exposomes), some of which are shown below, leaving out country analyses, multiple tests and optimization of their model, and a blitz of sensitivity analyses.

There were a couple of nuances from the analyses worth noting. Two categories—migrants and gender inequality— showed blunting of benefit for multilingualism. That may be due to the fact that migrants are forced, rather than electively choosing to learn a new language, and for women experiencing social constraints.

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Interpretation and Implications

The are some important limitations to acknowledge. The robust analyses are providing strong associative links, not establishing cause and effect. The results are restricted to European countries where multilingualism may be more common and not representative of other parts of the world. The national level data used for categorizing monolingualism or multilingualism is not nearly as helpful as what would have been garnered at the individual level. Furthermore, we have no idea when a person learned a new language and how proficient or how frequent the language was spoken. All of the prior data would have suggested the benefit of multilingualism related neuroplasticity is enhanced over time, when adopted at younger ages, but data in the new report leave this matter clouded

The use of the BAG here is of interest, providing a metric to show protection from accelerating aging. But that could be corroborated by brain clocks, using proteomics to determine the brain pace of aging, which have previously and consistentty been shown to be a critical determinant of lifespan and healthspan (Figure below, as previously reviewed in Ground Truths). Other biological clocks such as DunedinPACE using methylation would also be helpful.

So, while there are a few holes in the story, the new study takes multilingualism to a much higher tier of respect for it representing an independent and modifiable risk factor for healthy aging, well beyond cognitive function that previously has been the focus. In my SUPER AGERS book I reviewed all the known— what I called “lifestyle plus factors” —since there are so many beyond exercise, diet and sleep. I would now add multilingualism, based on this new report, as a lifestyle plus factor. It is certainly low cost and eminently scalable. Yes, there are residual uncertainties, but there’s a lot more here than any anti-aging supplement, or evidence of benefit from a longevity clinic or company, and at no risk. As the accompanying commentary asserted: “multilingual usage across the lifespan could be as important as campaigns that promote physical activity, or smoking cessation.” I’m not multilingual, although I took French through college. Now I’m regretting that I didn’t keep it up and even contemplating learning it and using it again. You folks who learned a 2nd (and 3rd) language as a kid and still use it are the lucky ones!

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This is about a seminal paper published in Nature today that provides compelling data for how mRNA vaccines can synergize with immunotherapy to improve survival outcomes in patients with advanced Stage IV cancers. It stems from an earlier observation by these researchers that patients undergoing immune checkpoint inhibitor therapy for cancer seemed to have better results when they had recently received a Covid mRNA vaccine. Their previous paper in July in Nature Biomedical Engineering invoked the role of Type 1 interferons for sensitizing immunotherapy in animal experiments.

In recent days, there’s been some media coverage on the presentation at the European Society of Medical Oncology meeting in Berlin but that fell far short compared with what the publication provides. In this Ground Truths edition I’ll get into the 3 major parts: (1) a thorough dissection of the mechanism, (2) the striking effects in clinical cohorts, and (3) the important implications for the future of cancer therapy.

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The Mechanism of Covid mRNA Vaccines in Cancer

This summary was pieced together from extensive work in preclinical models, prospective research participants, and patient outcomes from retrospective cohorts.

1. It has nothing to do with SARS-CoV-2 spike or Covid per se; when that spike protein was removed (and replaced by a cytomegalovirus antigen pp65), the same benefit was seen. It’s a function of the mRNA/lipid nanoparticle (RNA-LNPs) package that unleashes a big Type 1 Interferon response (setting off the alarm). Further, when flu and pneumonia vaccines were tested without the RNA-LNPs, there was no benefit. The Moderna vaccine, which contains more RNA, had more of an in vitro effect than the Pfizer/BioNTech vaccine, reinforcing the impact of the RNA component, but without differences in clinical outcomes. When Type 1 interferon was blocked, there was no benefit. The magnitude of the acute bump in Type 1 interferon, as determined from blood samples of healthy participants who received Covid vaccines, was 280-fold!

2. “Cold” tumors are invisible, evading the body’s immune system, without infiltration of immune cells, and much less likely to respond to immunotherapy. As seen below (from the publication), the innate immune cells (such as plasmacytoid dendritic, pDC, in blue) are activated, and that primes T cells (green).

3. The T cells can now get into the tumor, making it “hot,” and the tumor cells respond by increasing their shield, which is PD-L1 (programmed cell death ligand-1) intended to suppress T cell activity. That’s perfect—all teed up now— for antibodies to PD1/PD-L1, the immune checkpoint inhibition, to take down the shield, and sets up the T cells to kill the tumor cells. Biopsy samples confirmed marked increase in PD-L1 expression after mRNA vaccine, not seen without this trigger.

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   The Clinical Benefit of mRNA Vaccines With Immune Checkpoint Inhibitors

   Using a time window cutoff of 100 days from a Covid shot to immune checkpoint inhibitor therapy, as compared with unvaccinated individuals or treatment outside this time window, there was a striking benefit for 2 types of advanced, metastatic cancer: non-small cell lung cancer (NSCLC) and melanoma. The graphs below show marked improvement in 3-year survival with Covid vaccines, ranging from 40-60%! For example, for Stage IV NSCLC at top right corner there was a doubling of survival at 3-years. These findings were corroborated by very poor response to ICI for patients with NSCLC tumors pre-pandemic, along with differences in progression-free survival for Covid vaccine vs unvaccinated.

   

   When the time window was altered from 100 days to 50 days within receipt of a Covid vaccine, the results for ICI benefit did not differ for clinical outcomes. In context, such 3-year survival improvements, with RNA-LNP plus ICI, in these 2 types of advanced cancers were not at all expected, far exceeding expectations. Could the dramatic survival benefit for these widely metastatic cancers be exaggerated due to the retrospective nature of the data and analysis, and the arbitrary time windows of 50 to 100 days? That can only be resolved by additional, dedicated prospective studies..

   Implications

   The unanticipated, added benefit of vaccines beyond their intended effect is becoming a theme, as we recently saw with herpes zoster vaccines vs shingles. As I previously reviewed, 3 natural experiments consistently finding a 20-25% reduction of dementia and Alzheimer’s disease. That magnitude of associated protection will soon be further confirmed with 2 additional natural experiments. If the shingles vaccine were a drug to prevent dementia, it would be considered a blockbuster. But in contrast to mRNA vaccines in the new report, we don’t know the mechanism. The speculation, which is certainly reasonable, is that the Shingle vaccines rev up the immune system in a favorable way to suppress brain inflammation, but details and proof for that are lacking.

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   The current paper established the mRNA-nanoparticle mechanism through multiple experiments, dissecting what could be considered every angle: the principal role and huge spike of Type 1 interferons, the lack of effect by vaccines without mRNA-nanoparticles, the heightened expression of PD-L1 confirmed in tissue biopsy induced by RNA-LNPs, all setting up immune checkpoint therapy to come in for the kill of tumor cells. This was the most impressive and compelling part of the publication.. Turning cold tumors into hot ones.

   We will need to see the large clinical outcome benefits independently replicated and extend to other advanced, “cold” tumors. If that indeed holds up, then we have a whole new alternative to personalized neoantigen vaccines. Why is that so important?

   

   There have been remarkably successful in preliminary small studies of patients with advanced pancreatic cancer, renal cell carcinoma, melanoma and others as recently reviewed here. But unlike a “universal” mRNA-lipid nanoparticle vaccine that is off-the-shelf, making a personalized neoantigen vaccine is laborious, expensive, and time consuming. As shown below, it requires sequencing tumor cells to define the specific proteins on the cell surface (neoantigens) that will be put into the individualized mRNA-nanoparticle vaccine to rev up the patient’s immune response, in combination with immune checkpoint inhibitors.

   

   It certainly is possible or even likely that the personalized neoantigen vaccines, as compared with generic mRNA-lipid nanoparticles, will be more potent in stimulating the tumor-specific immune response. But the effect seen in the report raises the question as to how much difference will be seen, and the potential of using the universal mRNA as a quick primer of the immune response while the neoantigen one is getting made. There is also hope for off-the-shelf neoantigen vaccines in the future, no less the ability to use these vaccines in people at high-risk for cancer for prevention.

   To emphasize, the mRNA-nanoparticle platform is not conceived as a stand alone treatment for cancer. It can be seen as a path to transforming cold, immune evasive tumors into hot ones, and setting up ICI drugs or other interventions to strengthen the immune response and achieve cancer cell destruction. The array of those interventions keeps growing, including engineered T cells (or engineering other cells such as natural killer), tumor infiltrating lymphocytes (TILs), antibody-drug conjugates, and more.

   In closing, the discovery of mRNA-lipid nanoparticle action to help treat refractory cancer can be viewed a major unforeseen step forward. Of course, there is more work to be done, as is always the case. But this finding comes in the wake of drastic cuts by the US Health and Human Services for the study of mRNA vaccines, which were already gathering encouraging data for many other infectious diseases, autoimmune conditions, rare diseases (via genome editing) and cancer. The versatile mRNA-NP platform is one of the most important advances in biomedical history, reinforced by today’s Nature paper. We should be building on its extraordinary life-saving pandemic success, not turning our back on it!

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   That makes the work involved in putting these together especially worthwhile.

   All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access. No ads.

   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.

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Background: Two Threads of Life Science Converge

By the late 1990s it was noted that there was something unusual about the lifespan of naked mole rats. In 2002, Drs. Rochelle Buffenstein and Jennifer Jarvis, comparative biologists, published “A New Record for the Oldest Living Rodent” for the naked mole rat, living over 27 years, about 5 times the maximal lifespan of mice or rats. In the past 2 decades since this discovery, much work done to understand their longevity and remarkable resistance to age-related diseases. Their heart, kidneys, liver, eyes and bones remain youthful. Cognitive function is preserved and they do not develop cancer (only 5 cases in over 3,000 necropsies). Some have lived up to 39 years of age. It has been shown that the naked mole rat lifespan defies Gompertz’s law for not having an exponentially increasing risk of death as they get older—the naked role rat is considered a “non-aging mammal.” Their existence is almost completely underground, moving around in tunnel systems. They are certainly not attractive! (Figure below) They are hairless, buck-toothed, wrinkly, and can survive without oxygen for 18 minutes. Known as extreme xenophobes, they only seem to die when they beat each other up. Owing to the unique features of healthspan and lifespan, they are considered the supermodel organism for understanding these critical biological features.

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But until now, we didn’t know the underlying mechanism for how naked mole rats lived so long and so healthily. This week, in Science, Yu Chen and colleagues from China published a compelling case for what explains the naked mole rat story.

Before we get to that, let’s go to a major basic science discovery that was awarded the 2024 Lasker Prize (considered pre-Nobel). Last year’s basic medical research prize recipient was Dr. Zhijian Chen of the University of Texas, Southwestern, for the discovery of cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase (yes a mouthful, thank goodness for acronyms). In back to back papers in Science in 2012 and 2013, Chen and colleagues identified and described cGAS and the pathway. It serves as a danger sensor, predominantly present in the cell cytoplasm, detecting penetration of foreign DNA from a virus or bacteria, or damaged DNA in the cell. Once danger is sensed, cGAS is activated and through cGAMP there is activation of STING, which stands for the stimulator of the interferon gene. This critical step leads to production of Type I interferons, a principal component of our innate immunity (simplified Figure below). Recall that with SARS-CoV-2 infection, Type 1 interferon, our first line of defense, provided critical protection, such that people with autoantibodies to type 1 interferon were highly vulnerable to severe, life-threatening Covid.

You can also see this pathway’s role in promoting inflammation, cell senescence, and death. Since the discovery in 2012, the cGAS-STING pathway has been implicated in many autoimmune and age-related inflammatory diseases, including cancer and neurodegenerative.

cGAS and the Extension of Healthspan and Lifespan

In the new report, the properties of cGAS for the naked mole rat were compared with mice and humans in cultured cells. When there was DNA damage in cells, the naked mole rat’s cGAS behaved very differently, engaged in DNA repair (known as homologous recombination, HR, for repair of double-strand DNA breaks) whereas in mice and humans HR was significantly reduced. This was accounted for by 4 missense mutations in the naked mole rat cGAS, and expression of the naked mole rat cGAS was assessed in human cells, in fruit flies, and in mice.

The unique naked mole rat cGAS (as expressed in cells and other organisms) had much less stress-induced cellular senescence, extended lifespan in fruit flies, and preempted organ degeneration in mice (via senescent markers in multiple organs), as further reflected by less frailty, less graying of hair, and significant reduction of blood levels of inflammation (Figure below, NM-R-naked mole rat, E/D is their 4 amino acid changed version and 4 mut, E/D is without the mutations) To further prove the impact of the 4 amino acid substitutions, these amino acid changes were reverted via human cGAS expression and all the protective effects were lost.

Accordingly, there are striking—opposite—changes between the function of cGAS in humans (and mice) compared with the naked mole rat, as schematically shown below. In humans without the 4 amino acid mutations, cGAS suppressed DNA repair. In naked mole rats, working through DNA repair factors P97, FANCI and RAD50, cGAS establishes tight binding of chromatin in the nucleus, HR promoting genome stability, and reducing inflammation.

To sum up, the Science paper was a comprehensive assessment of the impact of naked mole rat’s cGAS in multiple species, with or without the 4 key mutations. Independent of the new report, a recent preprint by Martinez and colleagues looked at mice with knockout of cGAS (cGAS KO) and demonstrated shortened lifespan and increased inflammation in multiple organs, stemming from genomic instability (loss of chromatin organization and de-repression of transposable elements known as “jumping genes”).

That independent corroboration of the new report strengthens the assertion that the cGAS is a fundamental pathway underpinning healthspan and lifespan in mammals, and that the 4 amino acid changes in the naked mole rat are the most likely explanation for their unique outlier status.

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The cGAS-STING Pathway in Clinical Trials

While this pathway is implicated in age-related diseases, the problem here is the duality of the therapeutic challenge. The path to Type 1 interferon production, the first line of defense of our innate immunity, further leads to immune cell recruitment and release of chemokines, which can be good or bad. On one hand, the cGAS sensor to detect DNA damage would seem vital for mounting defense against invading pathogens but also amping up anti-tumor immunity, which is why cGAS agonists are being developed vs cancer. On the other hand, blocking untoward self-directed immunity and chronic inflammation would be achieved by inhibitors of cGAS-STING. For example, cGAS-STING signaling has been tied to age-related macular degeneration, a leading cause of blindness, and systemic lupus erhythemosus (SLE). These could theoretically be prevented or suppressed by blocking the pathway. The field of neurodegenerative diseases is actively being pursued in preclinical work (Figure) with cGAS-STING blockers via many different small molecule (pill) drugs.

Here’s a sample of some of the clinical trials underway to give you a sense of how the field is progressing. Most of the trials are in cancer, and there are at least 12 more of those I haven’t put in the Table summary that are testing the pathway in combination with immune checkpoint inhibitors (ICI) to further rev up the immune response vs advanced or refractory cancers.

Concluding Remarks

I’ve been following the naked mole rat story for decades and it was exciting to see this new report which helps explain what’s behind this legendary animal’s unique healthspan and lifespan. Many other mechanisms have been proposed over the years, but none have had such comprehensive, state-of-the-art assessment in multiple species and a form of independent replication. The convergence of the finding underpinning organismal longevity with the discovery of the cGAS pathway takes the interest to a higher level, no less for potential clinical applications

However, it’s much trickier to translate this to a way to promote healthspan and longevity in humans. The naked mole rat lives underground and has a radically different environmental exposure versus humans. It could theoretically tolerate the inability to sense foreign DNA of pathogens and be so well suited for prioritizing DNA repair and suppressing inflammation. If we could do a bridge recombination cGAS genome edit of the 4 amino acids, as Patrick Hsu quipped on X, (below) what might be in for? Serious infections? Autoimmune diseases?

The very delicate balance of the ongoing clinical trials—to promote or block cGAS-STING—tells us about this tradeoff, and what could turn out to be a very narrow therapeutic window. Like a Goldilocks tale. On the other hand, these small molecules, both agonists and antagonists, appear to be very potent in vitro and well tolerated in Phase 1 studies, so we’ll have to see how they will pan out. It doesn’t have the look of the GLP-1 family of drugs which are all agonists of naturally occurring hormones and have outperformed all expectations to date (and likely more to come). I wish it were more straightforward for this class of drugs like the GLP-1s! It’s still very early for cGAS-STING pathway drugs, but watch this space.

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One other thing before you go. Many of you started subscribing to Ground Truths during the height of the Covid pandemic. Please know I still follow Covid related developments very closely, but unless there is important new stuff, I mainly cover major biomedical advances here (or debunk stuff like peptides or protein consumption overdose). That said, If you haven’t gotten a Covid booster, consider doing that. There’s a major wave brewing in England with no change in variants (it’s XFG, the same as what is highly dominant in the US). That is most likely attributable to waning of immunity (it’s not winter yet!) by process of elimination. As in the US, there are substantially less people who are getting boosted. What happens in England (as in Covid waves) rarely stays in England. Below are the updated Covid hospitalization data from Prof Christina Pagel who writes a very good Substack, often highlighting critical US issues even though she’s from the UK. I recently got Novavax for the first time and had no reaction whatsoever, a welcome change from all the previous shots that I’ve had.

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Primary Prevention means a disease or condition is averted. The term was coined and introduced by Leavell and Clark in the late 1940s. Now, about 75 years later, we’ve yet to achieve any substantive primary prevention with the notable exception of vaccinations that prevent infectious diseases. Of the 3 major age-related diseases that I focused on in SUPER AGERS—cardiovascular, cancer, and neurodegenerative—we have not prevented the latter two. Remember screening for cancer (such as mammography, colonoscopy, PSA, or total body MRI as some have advocated without adequate data) is a secondary prevention, with the objective of finding cancer at an early stage. Nothing meaningful has yet been shown to prevent neurodegenerative diseases. While there has been some preemption of cardiovascular disease with the use of lipid panels and cholesterol lowering drugs, heart attacks (and heart disease) and strokes remain the number 1 and 3 medical causes of death in the United States, respectively. And heart disease deaths are ticking up, adjusted for age.

Instead our healthcare now is centered on treating these diseases, which has limited success for many cancers and even less, thus far no disease-modifying impact, for neurodegenerative diseases (Alzheimer’s and Parkinson’s). No less, there’s the profound economic benefit of primary prevention for reducing the cost of such treatments, such as tailored oncology drugs or support of people with dementia in long-term care facilities. I hope this brief review will convince you that primary prevention is a great and largely unfulfilled need, that in light of recent advances it should be given the highest priority. The key problem is that we haven’t had the ability to do it. Until now.

This Ground Truths post is about the new and exciting opportunity for achieving primary prevention. We’ll start with a groundbreaking study just published in Nature by Moritz Gerstung and his colleagues.

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A Large Language of Health Model Predicting Individualized Risk for >1,000 Diseases — in Multiples and When

What if an individual’s arc of health events was like a sentence, a sequence whereby you could predict the next condition like you would with a transformer architecture A.I. autocompletion of words (hopefully a helluva lot better that we have now on our phones!)? That is the essence of generative A.I.’s power for text, using tokens of words (and word fragments) with extraordinary contextualization, giving it the ability to write high quality text, even books. Delphi-2M is a transformer, large language model (GPT-2 derived) learning the language of human health, that does exactly that but the tokens are based on diseases, sex, lifestyle and other related factors. It was built from the records, with long-term follow up, of 400,000 participants in the UK Biobank and externally validated in the Denmark population of 1.9 million people. Despite the participants in the UK Biobank being much younger, there was almost no difference in the Delphi-2M’s model performance for predicting diseases without any change in the parameters of the model. The input data included hospitalizations, primary care visits, self-reported information, and death registries.

Across >1,000 diseases, which is essentially the complete list of International Classification of Diseases (ICD-10), the Delphi-2M AUC (area under the curve, performance) was 0.76, and 0.70 over a 10-year span for prediction. The model was as good or slightly better than the best current single disease predictive models for dementia or heart disease (see below), and most others, but worse for Type 2 diabetes using HbA1c as single marker. Importantly, it predicted not just one but the multiple diseases (←when that risk was present) for an individual and the timing of appearance for each disease.

Below is the prediction of 10 diseases/conditions by the Delphi model and actual occurrence, specific to age.

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For the outcome of death, the AUC was 0.97, age-stratified, for both sexes.

Using synthetic data to project a person’s future health from age 60 to 80, there was little reduction in the model’s performance (0.74 AUC).

The model did not include many other layers of data such as polygenic risk score (PRS) or genome sequence, biomarkers, unstructured text from medical records, epigenetic or organ clocks, and several other potential layers that could be added. You can see how adding polygenic risk scores (at left below) or biomarkers (at right below) to the Delphi model took it even higher in accuracy for many diseases.

I won’t go into all the work put into their model explainability, with attention maps and ablation, but suffice it to say the success for predicting what disease(s) and when was tied, in part, to identifying patterns of clusters from the very large of sampling of people’s longitudinal health data.

Of course, there are many limitations to Delphi-2M, such as biases related to inputs of data. For example, people who were hospitalized had clusters of diagnoses attributed to being in a hospital, a type of data collection bias. There are ICD-10 disease token biases. And there were marked differences between healthy, younger volunteers in theUK Biobank vs sampling of the Danish population, but surprisingly little difference in model performance.

Other Related Major Advances

Here I’m going to highlight a few new papers that have come out in recent days and weeks that further bolster the case I made for primary prevention in SUPER AGERS. It’s inevitable—we’re going to age. But that doesn’t mean we have to manifest age-related diseases.

Personal Health Agent (PHA)

Instead of a single model like Delphi-2M that would be theoretically used chiefly by clinicians, Google DeepMind and Columbia University researchers published a multi-agent A.I. team approach that would process, interpret and be interactive with one’s personal electronic health record (including unstructured notes, labs, and reports) and wearable sensor data. Along with that the best sources of up-to-date medical knowledge. Employing a user-based design, from real world data from Google health queries, Fitbit forums, and surveys about personal health goals, a critical user journey was defined, divided into 4 areas:(1) general health knowledge; (2) personal data insights; (3) wellness advice; and (4) personal medical symptoms.

It’s a tall order because an analytic approach for doing this represents a formidable, previously unmet challenge. Just time-series analysis of multiple continuous data outputs from sensors had previously shown little progress. But with 3 A.I. specialized agents, one with expertise in data science, another a medical domain expert, and a third working as a health coach agent, the personal health agent performed exceptionally well according to benchmark ratings by human health experts (see the performance wheels below). The teamwork is coordinated by a project manager or orchestrator (bottom schematic) that harmonizes the work and output of the 3 agents across 4 steps. This is an important advance since we know lifestyle factors are critical for helping to prevent diseases, but we have not had a way to work with the multimodal data, get intelligence from it. Previously, we’ve basically been data collectors and have had limited interpretability restricted to one type of input (such as sleep data).

The PHA performed quite well. Compared with base model (Gemini), 65% of the summaries generated were found useful by clinicians compared with 30% of the base model.

Experts ranked the PHA as the best quality and most effective system for helping users achieve their goals in 80% of cases compared with 4% for a single-agent or 15% for a non-orchestrated multi-agent parallel system.

These are a sampling of evaluations of PHA, which, in general, was seen as more favorable for clinician reviewers than users, but both trending in the same direction. Of note, the PHA’s memory set up for long-term coaching and interaction, picking up where it left off, an essential feature for a PHA.

Again, there are many caveats and limitations including algorithmic bias due to inputs, security, the added consumption of computing power, data privacy, security, and over-reliance of the PHA by users. It clearly will require clinician oversight but can be seen as complementary to the Delphi-2M for directly helping patients. The most important limitation is that it has not yet undergone a prospective study in the real world of medicine compared to not having a PHA with the endpoint of pre-specified health outcomes.

Epigenetic Organ Age Clocks

I have written extensively about proteomic organ clocks and how they can give us considerable insight within an individual for accelerated pace of aging of our brain, heart, kidneys, liver, lungs, arteries and the immune system. A new report shows this can also be accomplished from methylation markers derived from a single blood sample using machine learning and A.I. integration with clinical biomarkers. Insights on aging for 11 organs or systems , as seen below, can be derived. Knowing that a person’s organ or immune system is out of step with the rest of their body for accelerated aging may be considered a tipoff to guide preventing a disease. For example, if the immune system has become senescent in a person, the risk of cancer will substantially increase. Recall we have not had any clinical way to assess the immune system until these clocks have arrived (and there’s more to come). The complementarity with proteomic clocks is a way to see if there is alignment, and both these tests will be inexpensive and likely commercially available soon.

Continuous Protein Monitoring (CPM)

Professor Shana Kelley and colleagues at Northwestern University published in Science an ingenious continuous, real-time sensor that used DNA strands to bind tightly to any protein circulating in the body, and electricity to get the protein off and assay it. Those of you who have tried continuous glucose monitoring (CGM) will know well how this works, applying the sensor just under the skin to sample interstitial fluid, then relaying your data to your smartphone. CPM was demonstrated in the diabetic rat model for tracking inflammation markers of interleukin-6 and tumor necrosis factor (Figure below, LPS is lipopolysaccharide). Last week I had a conversation on Ground Truths with Prof Kelly about this important discovery that has implications for prevention across many diseases (cardiovascular, autoimmune, neurodegenerative). She and her team have a review paper that will be published later this month that lays it all out and is outstanding.

The Template for Primary Prevention

As I presented in SUPER AGERS, we now have the means for defining high-risk individuals for the major age-related diseases. By using multimodal A.I. to integrate all the layers of a person’s data, we’ll be able to know whether a person is at high-risk and get an impression of the temporal arc of when a disease will appear (clinically manifest). Below is the example for cancer. We’ve already seen a number of studies demonstrating A.I. partitioning of high-risk and early detection of pancreatic cancer (among other cancer types) with much less depth of data than presented here. As you know, this is a highly fatal cancer which, in over 90% of cases, is only currently diagnosed at late, metastatic stages.

Alzheimer’s is the most dreaded disease for most people. Following a similar template as above for cancer (presented in SUPER AGERS), we will be starting a large randomized trial soon to prevent Alzheimer’s in people at high-risk due to their family history, APOE4 status, and polygenic risk score. Now that we have blood biomarkers that are modifiable like p-tau217, we’re in a powerful position to move forward.

Concluding Remarks

Here’s the contrast. At left below is state-of-the-art “primary prevention” today. Even that short list is not followed by a large proportion of primary care physicians or their patients. With the exception of preventing infectious diseases, it has little, certainly insufficient impact to prevent non-communicable, ,major age-related diseases.

At right, the future ,with many layers of new data that are already available (like p-tau217, polygenic risk scores, genomics). And many that will be available soon, such as organ clocks, an immune system clock and comprehensive assessment, A.I. of the retina, your images, and labs (trends in your “normal” lab values without an asterisk can be quite meaningful with A.I., as I previously reviewed). Eventually CPM and digital twin information resources (learning from nearest neighbor in our species) will be added to take primary prevention to an even higher level.

We’re at the dawn of primary prevention. Not only are there many new layers of data—organ clocks, biomarkers, genomics, biosensors—but we have multimodal A.I. and agentIc A.I. to analyze the data. For the first time, we are seeing a large health model (Delphi-2M) that has learned the grammar and language of health, tokenizing it to predict diseases with temporal anchoring. We’ve gotten used to large language models that predict the next word in a sentence, but just imagine how powerful a large health model (LHM) will be when all the other layers of data beyond those utilized in Delphi-2M are integrated. Yes, 0.76 AUC performance for prediction across all diseases isn’t great, but this is just the beginning. From Delphi-2M, we learned that person’s health story can be projected 20 years ahead. This represents a jump from my prior piece on precision medical forecasting. Future models will keep improving on precise medical forecasting.

At the same time, we’re seeing the most advanced personal health agent that has yet been developed and validated, which can incorporate layers of data not previously utilized, with interactivity and long-term memory that may help promote healthy lifestyles for users. No, it won’t work for everyone, but given poor adoption of healthy lifestyle factors (for example, 75% of Americans do not even fulfill the minimal recommendations for physical activity), it would be hard to think it won’t help to some extent.

There’s currently a lot of negativism about generative A.I. I get it. But the new era of primary prevention would not be possible without it. It will take time to get this to be standard of care, that is real prevention, but I believe it will ultimately wind up being seen as the most important contribution of A.I. for promoting human health.

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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!

I will come back to this important Figure below later in the post, from an important study in both mice and people, demonstrating that high protein intake accelerated atherosclerosis and increases cardiovascular risk, and provided the underlying mechanism. In contrast, The Daily podcast stated: “Well, it’s unlikely that eating too much protein is actually going to harm you. Unless you have a specific kidney issue, we can eat a lot of protein. And it’s not going to be bad for you.” It turns out there’s no shortage of data to refute that assertion made by the New York Times (which produces The Daily).

Let’s get into this topic by answering 3 questions:

1. What is driving the protein obsession?

2. What are the data for high protein intake health benefits?

3. What are the safety concerns regarding high protein consumption?

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1. Driving The Protein Obsession

The most recent published 2024 International Food Information Council annual survey of Americans found that 71% want to increase their protein intake, more than any other dietary constituent or vitamin. That number for protein was 52% in the 2022 survey. The number of Google searches for “high protein” peaked in 2025.

It’s no wonder. Social media is chock full of protein promoters. A search of TikTok for “200 grams of protein a day” gets dozens of instructional videos. A survey of non-professional athletes taking protein supplements found that 40% get their information from social media. The Daily asserted that there are two main influencers driving the high protein craze:

“So the protein is going to be a substance that helps you improve your health, and not only lose weight, not only gain muscle, but also being the best physical version of yourself. And the two biggest and most influential names here are Peter Attia and Andrew Huberman. And these two guys are really extraordinarily influential in the nutrition space right now, the wellness space……Protein is a big part of it for both of them.”

The podcast centered on the wildly successful David bars (pictured below), which are promoted by these 2 influencers who each have a stake in the company. The bars are unique for packing in 28g of protein into 150 calories which are on track to sell $180 million in 2025. The method for achieving this high density, lower calorie product hinged on using EPG, “a modified plant fat that moves through your digestive system mostly undigested.” One problem with the David bar is that, by definition, it is an ultraprocessed food, i.e. not exactly rigorously perfected protein as proclaimed on the website). David Protein, the David bar company, bought Epogee, which makes EPG, to own the patent rights, insure supply, and lock out competition. David Protein recently launched David Cod, which sells four 6 oz pieces of frozen cod for $55 and plans to become a/the platform for protein.

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The pervasive call for higher protein intake stems from the assertion that people are not getting adequate amounts in their diet, namely the 0.8 g/kg/day recommended by the National Academy of Medicine and the World Health Organization. Yet the most recent data from USDA says the federal protein recommendation is exceeded by more than 55% of men and 35% of women. Peter Attia advocates for 2.2 g/kg/day (or 1 g/lb/day) of protein intake in his book Outlive. That translates to almost 3-fold the established recommendation. Attia “declined multiple requests to comment” in a recent New York Times piece entitled, “The More Protein, The Better?” written by Alice Callahan, who has a PhD in nutrition. Regarding the need to increase protein intake 2-3 fold per day, Stuart Phillips, a leading expert on protein, energy, and building muscle mass, who is a professor at McMaster University in Canada, said “It’s baloney. But there’s a generation, particularly young men, and now an increasing number of young women, who are absolutely brainwashed by what they hear online.”

Some of the confusion on the right protein intake amount depends on the physical activity of the individual, for example sedentary vs weightlifter. Phillips, who has published extensively on this topic, recommends higher protein intake for weightlifters at 1.2 to 1.6 g/kg/day which is based on the data we’ll review next.

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2. The Data for High Protein Health Benefits

In the Table below, I pulled together all the published meta-analyses and systematic reviews that I could find on the topic of high protein intake. The senior author of the top 2 is Stuart Phillips. The number of randomized clinical trials (RCTs) and the number of participants (N) is shown along with the relevant features of the participants and the primary conclusions. The endpoints of these trials included muscle mass, muscle strength, and lean body mass.

Simply put, there are no data to support more than 1.6 g/kg/day of protein intake. Some of these studies were in older adults with mixed data (Nunes study no benefit for older group; ten Haaff no benefit age 50+ over resistance training; Liao benefit in older men on top of resistance training). Likewise, the data are mixed for overweight and obese participants. The findings across all the studies, most of which are quite small in sample size, show marked inter-individual variability. The design and the analysis of the trials are compromised by lack of controlling for calories in the diet, physical activity, and many other confounding factors, along with flaws of interpretation.

The Morton study is the most widely cited, but the main graph shown below is problematic. The y-axis is for the change in fat-free mass (FFM) and the x-axis plots total protein intake.

As aptly pointed out by Nassim Taleb and others on X, the vertical line drawn down to 1.6 g/kg/d is an illusion or myth, without statistical basis. If you take away the vertical and horizontal lines from the graph, you see it is a contrived regression, a scatterplot (below), that does not support any optimal level of protein intake. Moreover, the P value for the regression is 0.079, which is not significant.

What about the strong recommendation for high protein in older adults? In the 50+ group, as reviewed by ten Haaf and colleagues, the randomized trials show no benefit of high protein on top of resistance training compared with resistance training alone (the control group) for improved lean body mass and there is no heterogeneity. The boxes below are all aligned with 0.00, no difference) for the 12 trials reviewed.

So we don’t even know at this point whether resistance training alone is enough to improve lean body mass, let alone what is the optimal dose of protein intake in older adults. Despite much uncertainty, in Europe the recommendation is for people over age 65 years to increase their protein intake by at least 1/4th, or from 0.8 g/kg/d to about 1.2 g/kg/d.

Higher protein intake has been thought to promote satiety and help people reduce weight but even that’s still unclear. Multiple studies have shown the higher the protein intake, the greater the number of calories (energy) consumed.

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2. Safety Concerns Regarding High-Protein Intake

There are many observational studies that have raised the safety concerns for high-protein intake, particularly derived from animal protein, for increased risk of type 2 diabetes, cardiovascular disease, and higher all-cause mortality. A prospective study of ~44,000 women in Sweden followed for 15.7 years found an association of high-protein diet with heightened cardiovascular risk. In 2,441 men aged 42 to 60 years followed for 22 years, there was increased heart failure among those who had a high protein diet, especially if it was predominantly animal derived. We’ve long known that high protein intake is dangerous for people with kidney disease, present in 1 of 7 adults, but 9 of 10 people with reduced kidney function are unaware of it. A higher risk of all-cause death was noted in a secondary analysis of a randomized diet trial. Of course, a problem with these studies is that they typically rely on food diaries or memory of the participants.

In mouse models of 25 diets, high protein diets were linked with less longevity and healthy aging indexed to activation of mTOR (more on this below). Consistently it has ben found that low—not high—protein diets are associated with longevity and healthy aging in animal model experiments.

A review entitled “A Word of Caution Against Excessive Protein Intake” concluded: “Although high dietary protein intake can increase muscle mass during resistance exercise training in young adults, a high-protein diet does not have clinically meaningful effects on lean mass or muscle mass during weight maintenance, weight gain or weight loss. Moreover, increasing protein intake is not without risk and can have adverse effects on metabolic function.” Another expert review concluded: “habitual high-protein intake, without marked carbohydrate and energy restriction, is associated with increased cardiometabolic disease risk.”

Now let’s get to recent work that helps illuminate the risk. A leader in this field is Babak Razani and his team at Washington University. In 2020, in the experimental model, Razani and colleagues determined that high protein was shown to activate the mammalian target of rapamycin (mTOR) in macrophages, which promoted atherosclerosis progression by inhibiting the clearance of damaged mitochondria (mitophagy). More recently, the same group probed this high protein atherosclerosis question in mice and people . The essential amino acid leucine (essential amino acids are not manufactured in the body, only obtained from ingestion) was found to be the culprit, driving atherosclerosis (simplified graphic below). Please also refer to the top Figure of this post that extrapolates the increased risk of atherosclerosis and cardiovascular disease from the data, showing up at protein intake of 1.5 g/kg/day.

This work supports leucine as a casual link for high protein intake and promotion of atherosclerosis via activation of mTOR. The studies in people were small with acute challenges of very high protein intake (from 22% to 50% of energy) and resultant high blood levels of leucine, changes in their circulating monocytes with mTOR activation, also flanked by the striking increase in inflammation and atherosclerotic plaque in the arteries of mice (studies you can’t easily do in humans).

This leucine discovery is important because leucine is one of the 3 branched chain essential amino acids that is widely used as a supplement by people training and athletes and one with putative anti-aging properties. Which is remarkable since potently activating mTOR is just the opposite of rapamycin (that blocks mTOR), a drug that many longevity influencers take! Remember that leucine is one of the 3 essential branched chain amino acids which are unique since they are primarily metabolized by muscle, not liver. So leucine may be considered pro-inflammatory and a bad actor even though it is also tied to building muscle mass. I wonder how many of the longevity influencers are taking both leucine supplements and rapamycin.

There are other recent experimental model studies that extend these safety concerns. A metabolite of histidine (imidazole propionate, imP), another essential amino acid, from bacteria in the gut microbiome, has been shown to directly (causal) induce atherosclerosis, again through the same mTOR activating, pro-inflammatory mechanism as leucine (schematic below). People who eat diets of fish, poultry, leafy vegetables, whole grains, nuts and fruits have lower blood levels of ImP.

Another recent study found that high protein intake shortened lifespan and accelerated aging in a mouse model of accelerated aging (progeria)

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Concluding Remarks

The obsession with increasing protein intake is without basis. 85% of the US population consumes more than the 0.8 g/kg/day recommended daily intake (RDI) and nearly 25% are consuming twice the RDI (Figure). IOM is Institute of Medicine, now named National Academy of Medicine.

The body of evidence about protein does not provide support very high protein intake, certainly not in excess of 1.6 g/kg/day, twice the recommended dietary allowance. Even that high level is not adequately substantiated for the reasons reviewed above. I cannot find any high quality data (e.g. from any randomized trial among hundreds that have been done) to substantiate the ~3-fold RDI (1g/lb/day) recommendation of the very high protein promoters.

There are 2 key principles to keep in mind about protein intake. For one, unlike carbohydrates and fat, there is no way to store protein in the body. In the excellent new book Food Intelligence by Kevin Hall (a leading US nutrition expert) and Julia Belluz (due out in September) that I reviewed, Stuart Phillips points out: “You can eat a ton of protein. You can digest a ton of protein. But the key question is: How much can you use? And we don’t have a way of stocking away extra amino acids.”

The more protein you take in beyond what can be used that day, the more is wasted. The nitrogen from amino acids is removed to form ammonia, converted to urea, and excreted in your urine.

Habitual or chronic high protein intake is associated with epidemiological evidence of harm, and, at high doses, the studies I reviewed raise the concern about pro-inflammatory effects and increasing cardiovascular risk, promoting the process of atherosclerosis. The essential amino acid leucine has been identified as the main culprit, which is rich in animal products such as meat, eggs, and dairy products. Although not as high in density, plenty of leucine intake can be derived from vegetables such as beans, seeds and nuts. There is no reason to take leucine supplements, which could be harmful.

The second point is that eating extra protein does not build muscle. Protein doesn't power muscle. I’ll cite the funny post by Nassim Taleb that helps bring this point home.

Resistance training is the principal driver for building muscle mass and strength, not high protein intake. Not growth hormone (see my recent post on peptides).

I’m not a nutrition scientist. Neither are the two main influencers of very high protein intake who both have stakes in companies that sell protein supplements. Besides my citing of Stuart Phillips and Kevin Hall, who are highly regarded authorities, here’s Prof Ethan Balk on faculty at New York University on the 1 g/lb/day (2.2 g/kg/d) protein intake: “The bodybuilding community kind of swears by it. But there’s been less, if any, support from research on that.” Prof Luc van Loon at Maastricht University in the Netherlands on increasing protein intake for people strength training said: “Tripling it is far more than most people require.” Or Prof David Church at University of Arkansas for people who want to build muscle, 1.5 to 2 times the RDI can be supported, “Beyond that amount the effect of protein on muscle gain kind of plateaus.”

Many people ask me what do I do? As I wrote in SUPER AGERS, “If I’m going to be old, I’d rather be strong and old!” I’m a septuagenarian and do strength training at least 3 times per week, for 30 minutes or more, including use of bands, free weights, push-ups, chin-ups, and deadlifts. I weigh 180 lbs which is just less than 82 kg. It’s very easy for me to get 82 g of protein in a day with a largely plant-based Mediterranean diet, eating Greek yogurt for breakfast, nuts for snacks, and a salad with salmon or tuna fish or beans for dinner. When I occasionally add up the protein I take in during a day, it is typically 100 to 120 g, which is equivalent to 1.2 to 1.4 g/kg/d. It would be an arduous struggle for me to eat 180 g of protein a day (the 1g/lb/day, an unfounded recommendation). And that excess protein would just get excreted.

There’s simply no need or evidence to be preoccupied with your protein intake. While it is clearly a current craze and a big revenue source for protein promoter companies and individuals, it is not substantiated. I hope you will consider this review useful and that it may help liberate you from any fixation on high protein intake.

A quick poll (yes, muscle mass is a typo below; Substack gives very limited space for characters in the choices)

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1. Endothelial Inflammation

Since the early days of the pandemic, inflammation of the endothelium, the lining of the blood vessel wall, was recognized. Endotheliopathy (or endotheliolitis) was demonstrated in post-mortem specimens, schematically shown below, with activated platelets and proteins that operate in the coagulation cascade to increase the risk of clotting (coagulopathy). The inflammation could be engendered by either direct infection the virus into the blood vessel wall or the inflammation mediators (cytokines, chemokines) released throughout the body from Covid. The process leading to an inflammatory endothelium underlies clinical events such as heart attacks and strokes.

Indeed, Libby and Luscher authored a perspective entitled “COVID-19 is, in the end, an endothelial disease” making a strong case in the early months of the pandemic, when the primary focus was just on the respiratory system— that the blood vessel lining effect of Covid was central to its morbidity and mortality.

Since the many studies have added to the mix, showing the Covid-induced endothelial inflammation leads to leaky blood vessels (increased vascular permeability), abnormal vasomotor tone or dysregulation. that it can increase the risk of hypertension, has further exacerbation by abnormal lipids, and results in reduction of myocardial blood flow. Of course, the effects were not confined to arterial endothelium, but also seen in veins with risk of deep vein thrombosis, and the microvasculature. Our review of Long Covid cited the role of blood vessel inflammation and its sequelae as one of the principal mechanisms for this condition.

2. Coronary Atherosclerosis

It took longer for us to understand had Covid promoted atherosclerosis, even though an increase risk of heart attacks was noted in the first year of the pandemic. Now several studies in experimental models and patients have demonstrated this effect, not only in the progression of atherosclerosis but also in its initiation (schematic below, Figure).

Specifically, in post-mortem coronary artery specimens in confirmed severe Covid patients there was detection of the virus in macrophages and foam cells along with the finding of the SARS-CoV-2 antisense strand replicating In these cells, composing an infection fo the blood vessel wall, marked inflammation, and potentiation of plaque instability (schematic below).

Recently, from patients with repeat CT coronary angiograms (690 with Covid, without hospitalization nad 113 controls, without Covid), there was evidence of more arterial plaque progression (left panel, for one metric below) to high-risk non-calcified plaques, increased inflammation, and more major adverse cardiovascular events (MACE) (right panel) among those with Covid.

The accompanying editorial to this paper was subtitled “An Early Warning of a Potential Public Health Crisis.”

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3. Acceleration of Vascular Age

The new study reported 17 August in the European Heart Journal was a big project involving 18 countries, 38 centers, and enrollment of over 2,000 participants to measure (on a repeat basis at baseline, 6 months and 1 year) carotid artery pulse wave velocity (PWV), a metric that is an indicator of arterial stiffness..

There were many important findings from this work. The acceleration of early (accelerated) vascular aging (EVA) was not proportionate to severity of COVID. Although participants who required ICU hospitalization had an estimate of 10 years of EVA, those who were not hospitalized had the same—5 years of accelerated arterial aging— as participants who did require hospitalization. The EVA effect was only significant in women and there was a statistically significant interaction term for Sex X EVA. Symptoms of Long Covid were linked to EVA and vaccination was associated with protection from EVA (graphs below, respectively). All of the analyses were adjusted for potential confounders. Some people with early EVA had resolution at 1-year follow-up. There was no assessment for reinfection and this prospective study was largely conducted early in the pandemic. The accompanying editorialist wrote: "The..study makes the case that Covid has aged our arteries, especially for females."

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Concluding Remarks

The new report is the first to demonstrate Covid’s impact on accelerated arterial aging. PWV has been used in previous small studies of Covid, but they were not adequately sized (largest had only 140 participants) or with the extent of follow-up as the present report. Particularly intriguing is the predominant effect in women, that is unexplained. We know the risk of Long Covid is greatly increased in women (~2/3rd of cases, if not higher) and that the immune system and propensity to inflammation has been tied to both two copies of the X chromosome (and the XIST gene that inactivates one of the X chromosomes) and hormonal factors, such as estrogen and progesterone. About 80% of autoimmune diseases occur in women. It is possible that there’s more propensity for endothelial inflammation after Covid in women compared with men, which sets up more chance of stiffness, fibrosis, and features of EVA. Another factor acknowledged by the authors is that there is less survivorship among men, a bias that could have contributed to the marked difference by sex.

The new findings of accelerated vascular aging need to be independently replicated. PVW is only one way to estimate the aging of blood vessels. Another is a proteomic artery (organ) clock, as initially advanced by Wyss-Coray and colleagues and now by multiple other groups. The observed Covid effect on artery aging by one metric in one study is important, but it is necessary for more work to be done with different means of assessment to know for certain its impact and magnitude. And to understand the apparent sex-specific effect.

To summarize, we’ve now seen a third dimension of Covid’s potential effect on our arteries, from the early recognized endothelial inflammation, with its attendant propensity for clots (micro or macro), to promoting atherosclerotic plaque, particularly those with high-risk for rupture (precursor for heart attack and stroke), to now accelerated aging. These 3 dimensions are not discrete, but interdependent. Undoubtedly, we will learn more on the future impact of Covid on our vascular health, but for now we can say it is likely well beyond what is generally recognized or anticipated.

Covid is still with us, with a summer wave in the United States that fortunately is not nearly as severe as previous ones, likely accounted , at least in part, by the XFG variant, now dominant, not being more evasive of our immune system than prior SARS-CoV-2 variants. It is unsettling, however, to see the marked reduction of tracking Covid here (be it by genomics or wastewater) and the gutting of funding of mRNA vaccines and platform which have an enormous future role, not just vs infectious diseases, but also combatting cancer, autoimmune diseases and support for genome editing for rare diseases. This is beyond Covid denialism, also representing anti-science, negating the extraordinary progress we’ve made over the past 5 years. Even in the new report we see evidence that vaccination is associated with protection for accelerated vascular aging, which goes along with many other levels of protection, including Long Covid. ←More on that soon!

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All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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.

Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past three years. Just a week ago we just had nearly 50 interns (high school, college and medical students) present posters of the work they did over the summer and it was exhilarating!

“Lithium powers our phones, laptops, and electric vehicles. My guess is the brain might have utilized this unique electrochemistry before we did.”—Bruce Yankner, senior author of the new report

If you’ve been reading recent Ground Truths posts, you’ll know I have been focusing on Predicting and Preventing Alzheimer’s Disease, and the Breakthrough Blood Test for Alzheimer’s Disease. This week the prospects for reducing the risk of Alzheimer’s had another advance with a new and impressive study published in Nature by Bruce Yankner and colleagues at Harvard Medical School. In this edition of Ground Truths, I’ll review the key background on Lithium and what we’ve just learned from the new report. I’ll divide this into 3 questions: (1) What Did We Know?; (2) What We Know Now; and (3) What’s Next?

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1. What Did We Know About Lithium and Alzheimer’s Disease?

Despite lack of knowing its mechanism of action, lithium use for bipolar disorder (BD) and psychiatric conditions dates back to the late 1800’s and —lithium carbonate— was approved for BD by the FDA in 1970. Its use is associated with a range of serious side effects, including neurologic, kidney and thyroid, establishing it as a medication with a narrow therapeutic window. From 3 different lines of evidence in clinical research, there was support for a potential lithium benefit for relative protection against Alzheimer’s and dementia (~80% of dementia is Alzheimer’s) or preservation of cognitive function.

—Randomized Trials

There have been 4 small placebo-controlled randomized trials, 3 of which were included in a meta-analysis, shown below for lithium’s benefit on cognitive function. Besides being very small (40 to 90 participants), the trials varied for inclusion criteria, length of drug treatment (10 weeks to 15 months), endpoints, levels of blood lithium achieved, and many other factors. The direction was towards benefit for all 3 trials, but only one on its own (Nunes 2013) was statistically significant.

A more recent randomized, double-blinded, placebo-controlled trial published in 2019, again with a small sample of 61 participants, using lithium carbonate at low doses for 2 years, also supported the finding with less conversion from mild cognitive impairment to dementia by lithium (Figure below, NB: P=0.06 is not significant at the 0.05 level; other measures of cognitive function were statistically significant for lithium’s advantage).

Notably, there was an increase in the lithium group concentration of amyloid-β in the cerebrospinal fluid vs placebo, suggesting the drug was helping to promote its clearance.

Another randomized lithium trial at the University of Pittsburgh of 80 participants called LATTICE (Lithium as a Treatment to Prevent Impairment of Cognition in Elders) with 2-year treatment, PET and MRI imaging, has been completed and the results are currently pending.

—Evidence in Bipolar Disease

A report from Denmark of nearly 5,000 patients with BD, of whom 30% were treated with lithium, was associated with statistically significant protection from dementia, a link not seen with anticonvulsants, antidepressants, or antipsychotics. (Table below). It has been noted that lithium’s efficacy is diminished in older people with BPD, which may have something to do with the amyloid sequestration mechanism described below.

—Evidence from Drinking Water Exposure

Another nationwide study from Denmark assessed lithium exposure in the water for over 73,000 people who developed dementia and over 730,000 controls. As seen in the Table below, the higher the mean lithium exposure, the more relative protection.

2. What We Know Now

The new paper took an agnostic approach to metals in the human brain, assessing the concentration of 27 of them, and finding only that lithium (Li) stood out in both people with mild cognitive impairment (MCI) and Alzheimer’s disease (vs individuals no cognitive impairment, NCI).

Indeed, the concentration of lithium in human brains were markedly different (ratio of cortex to blood or in brain tissue,) as shown below. Notably, the levels of lithium in the brain from people with intact cognition is 1,000X lower than what are achieved with lithium treatment for BD.

With that background a series of experiments in mice with either lithium deficient diet or lithium repletion were undertaken, in Alzheimer model mice and aged (wild-type) mice, along with the effects of these manipulations on memory, learning, inflammation and related changes in brain cells and tissue.

The principal findings can be summarized:

1. Amyloid plaque-in the brain binds avidly to lithium and sequesters it (left panel below). That steals the lithium from non-plaque tissue and reduces its function. When the right lithium salt preparation is given (lithium orotate) that doesn’t get sequestered by amyloid, the microglia cell function is improved to clear amyloid-β (right panel below).

   

2. A lithium-deficient diet in the Alzheimer model mouse was pro-inflammatory with increased activated microglia (Figure also shown at the top of this post), marked accumulation of amyloid-β, and phosphorylated tau protein, loss of synapses, axons, myelin, worsened cognitive function and memory.

   

3. Finding a lithium salt that was much less likely to form ions and get sequestered by amyloid-β, turned out to be lithium orotate, markedly better than lithium carbonate, the drug that has been used in BD and that undergone previous clinical trials for cognitive function and progression to Alzheimer’s disease.

   

4. When compared with lithium carbonate, lithium orotate better prevented accumulation of amyloid-β, tau-phosphorylation, neuroinfalmmation and cognitive parameter decline.

5. Lithium orotate given to aged wild-type mice (not the Alzheimer’s model mice) reverted their memory to young adult (6-month) level, along with object recognition and maze tasks.

6. SIngle-nucleus RNA sequencing showed parallel changes of gene expression between the lithium diet deficient mice and human brain samples with Alzheimer’s disease. The enzyme glycogen synthase kinase GSK3β is activated and expressed by endogenous lithium deficiency. An inhibitor to this kinase may also provide protective effects.

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   3. What’s Next?

   The new study is the most impressive neuroscience of lithium published to date. It is comprehensive, mechanistic, and brings together compelling human and mice data (the latter from both the Alzheimer’s model and aging organism). The work also led to the discovery of a far better lithium salt that reduces the likelihood of being trapped by amyloid-β, following up the finding that sequestration is foundational to lithium’s effect. The point that very low doses of lithium would be expected to achieve salutary effects in humans is especially noteworthy, given the toxicity of lithium carbonate at high doses used in BD. Importantly, this extensive work would not have been possible without the support by multiple NIH grants now being subject to profound cuts, no less $2.6 billion specific to Harvard .

   The outgrowths of the new study go well beyond reduced brain inflammation and promoting amyloid-β clearance to reduce progression to Alzheimer’s disease, raising the question should lithium levels be assessed as a risk factor and might this also be extended to other neurodegenerative diseases, such as Parkinson’s.

   Lithium orotate is not naturally found in significant amounts in common foods. Should people start taking lithium orotate, such as the low dose of 5 mg now, widely available as an unregulated supplement? The answer is no, even though we’d anticipate it would be safe, without worrisome side effects as seen with considerably higher doses of lithium carbonate used for BD. Yes, it’s tempting, with the body of evidence presented here that exceeds supplements in common use, but we need a clinical trial to prove that the new study translates to a human benefit. If lithium orotate does work, we don’t know the right or optimal dose. Even 10 mg would be a huge dropdown from the usual dose for lithium carbonate, which for BD in adults is between 600 to 1,800 mg/day. The amount of elemental lithium in lithium orotate is approximately 1/5th of lithium carbonate. So doses of orotate between 5 and 10 mg may be insufficient to achieve the effect (10 mg of lithium orotate is equivalent to about 0.4mg of elemental lithium).

   As I previously discussed with p-tau217 and other blood markers, along with pace of aging brain clocks (using proteomics), it would be straightforward to do a randomized trial and see whether these surrogate metrics are favorably modulated by lithium orotate versus placebo. We hope to initiate such a randomized trial in the near future that would help illuminate whether low dose lithium orotate has efficacy in people.

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Thanks to many of you Ground Truth subscribers who helped put SUPER AGERS on the NYT bestseller list for 4 weeks so far. Here’s a new video of a fun conversation I had with Dr. Siddhartha Mukherjee on A.I., extending healthspan, and the book.

I’m also very appreciative for your reading and subscribing to Ground Truths.

If you found this interesting PLEASE share it!

That makes the work involved in putting these together especially worthwhile.

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All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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.

Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past three years. On Friday this week we just had nearly 50 interns (high school, college and medical students) present posters of the work they did over the summer and it was exhilarating! Some photos below

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I’ve recently written about the gut-brain axis and how the gut talks to the brain and the immune system. There’s a common thread, the vagus nerve, which as shown in yellow in the map below, connects the brain with various organs throughout the body, including rich innervation of the gut lining. Beyond the vagal circuitry, other neural connections connect the spleen, gut, liver, bone marrow and lymph nodes (←new review in Nature Reviews Immunology) can activate the immune system’s T and B cells, macrophages, dendritic cells, plasma cells, production of antibodies, and release of pro-inflammatory cytokines.

Below is an example of how the brain connects through the splenic nerve can rev up the immune system (PVN-paraventricular nucleus, AChR-acetycholine receptor, RAMP-receptor activity-modifying protein, TIMP-tissue inhibitor of metalloproteinase). The connections between the brain and immune system are not just neural mediated, but also occur via hormones and chemical signals, especially mediated via the brain’s hypothalamus-pituitary axis.

With that anatomic basis, let’s get into the new reports and advances.

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1. Just seeing a person with signs of infection activates our immune response!

This week in Nature Neuroscience Andrea Serino and colleagues published the results of 248 healthy volunteers who underwent virtual reality to see human avatar faces categorizing persons with signs of infection (coughing, rashes), one of fear, and another of neutrality (“Neural anticipation of virtual infection triggers an immune response.”). The participants underwent functional MRI, EEG and immune system studies. The infectious avatars activated the hypothalamic-pituitary axis which led to immune activation, replicated by flu vaccine administration, as seen below by innate lymphoid cells (ILC) and verified by multiple markers of lymphocytes. That wasn’t evoked by the neutral or fearful avatars.

2. An implantable neuroimmune modulation device for autoimmune disease

Last year Peterson and colleagues published a randomized, double-blind, sham controlled trial of an implantable 1 inch device to stimulate the vagus nerve in 60 patients with rheumatoid arthritis to show feasability and safety. Using the same double-blind, sham design, a Phase 3 trial was undertaken enrolling 242 patients with moderate to severe rheumatoid arthritis who had failed at least one advanced drug therapy (biologic or synthetic disease modifying drug). The device delivers stimulation for 1 minute each day and is recharged during 10 minutes each week wirelessly via a necklace (schematic below).

At 12 weeks, 35% of patients receiving daily stimulation vs 24% of the sham device achieved improvement in the ACR20 endpoint (American College of Rheumatology 20% response criteria). For the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) endpoint, the treatment group had a 27% response vs 16% in the control group. By 1 year, with crossover all to the active device, over 60% of participants had relief of joint pain and swelling. The main adverse effect was hoarseness, which occurred in 2% of participants due to the device implant.

SetPoint Systems, the company that commercialized the device, received FDA approval this week and that was on the front page of the New York Times.

The company has also published efficacy results for the device in the experimental model of multiple sclerosis and have already initiated clinical trials for inflammatory bowel disease in children and lupus and plans to do clinical trials for multiple sclerosis and Crohn’s disease.

This is an outgrowth of the pioneering work of Prof Kevin Tracey who has been the main force over 2 decades to push the field forward. His classic paper in Nature in 2002 entitled “The Inflammatory Reflex” advanced the concept that vagal nerve stimulation could suppress inflammation.

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3. The Alzheimer’s Disease Risk of APOE4 Carriers is Mediated via the Immune System

One copy of the APOE ε4 allele is present in about 20% of people and is the strongest genetic risk factor of late-onset Alzheimer’s disease. That discovery was made in 1993 but the mechanism for how the ε4 allele induces the risk has not been clear in the three subsequent decades. In Nature Medicine, Shvetcov and colleagues demonstrated that carriers of the ε4 allele have a proteomic signature denoting immune dysregulation. From machine learning of nearly 10,000 plasma samples and >1,300 cerebrospinal fluid (CSF) samples, there was convergence of many findings between plasma (shown below) and CSF, and a pro-inflammatory signature was seen. There was marked immune cell enrichment, predominately T cells, monocytes, and natural killer cells. This finding reshapes our understanding for how the APOE ε4 allele increases the risk of neurodegenerative disease.

Parenthetically, another clarification for an elusive mechanism of action (MoA), there was a reset for how metformin works. As the first line drug for Type 2 diabetes used for 60 years, there were many ideas for its MoA such as reducing glucose output from the liver. We just learned metformin relies on a pathway in the brain to exert its effect.

4. A Multiomics Study for Alzheimer's and Cerebrovascular Diseases

A new paper in Neuron examined RNA and epigenetic variants for Alzheimer’s (AD) and stroke (study schematic below) and found that the former was linked to dysregulated immune system omics, with a lead variant that enhanced expression of PTK2B in brain T cells. The evidence for altered adaptive immunity for AD was in marked contrast to the findings for omics related to cerebrovascular diseases, and provides yet another study highlighting the immune system’s status as off the track for AD.

Other Related Reports

A randomized trial of structured lifestyle improvement with coaching for an anti-inflammatory diet, exercise, as compared with controls who were self-guided, showed significant improvement in global cognition.

A study of ME/CFS by Akiko Iwasaki and colleagues, using plasma and CSF samples of affected individuals and matched controls, demonstrated 2 distinct immunotypes for this condition, which is characterized by many symptoms that are referable to the central nervous system.

A randomized trial of semaglutide (Ozempic) vs placebo in participants with HIV-associated lipohypertrophy, a pro-inflammatory condition (mean BMI of participants =33 ) was preprint published. The GLP-1 drug slowed epigenetic aging and the pace of aging across 11 organ and system clocks. This likely reflects the potent anti-inflammatory effects of these drugs, both systemically and in the brain. The significant slowing of the pace of brain aging (nearly 5 years) is shown below at right. As far as I know, this is the first drug in a randomized, placebo-controlled trial to demonstrate such epigenetic and organ clock findings. Clearly, we’ll need to see independent replication in healthy individuals who are not overweight or obese, but these results are nonetheless encouraging.

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Concluding Remarks

In my book Super Agers, I have a chapter on “Controlling Our Immune System” which goes through the ways we are taking control of our immune system like a rheostat. Dialing it down to achieve tolerance in autoimmune diseases, such as engineered T cells that bind to a protein on the surface of all B cells (CD-19). That has achieved remarkable success in a small number of individuals with several autoimmune diseases (lupus, multiple sclerosis, polymyositis, and others). In prior Ground Truths posts, I’ve reviewed other ways we can dial down the immune response, such as through the liver (!) or tolerogenic vaccines. Here, the studies on vagal stimulation have now validated yet another approach that we can suppress the immune system and inflammation and the indication for rheumatoid arthritis is likely just the beginning. Perhaps there will be simpler, inexpensive, non-implantable devices to achieve vagal nerve stimulation such as was anecdotally reported for Long Covid. We’re also learning about how the GLP-1 drugs can be used to block inflammation, awaiting the results of the EVOKE Alzheimer’s randomized trials next month.

Just as our armamentarium is expanding for suppressing the immune system, we’re seeing how it can be dialed up too. For example, the results of the 3 natural experiments of Shingles vaccines that consistently lowered the rate of dementia and Alzheimer’s disease, reviewed here, or how more aggressive ways to rev up the immune system are leading to heightened treatment success for refractory cancers. However, there’s a fine line for unleashing the immune system with the potential of promoting a self-directed or dysregulated state. Despite that critical concern, we’re making major strides in controlling our immune system.

Ironically, we still don’t have a way to measure it routinely, as I conveyed in Why We Need an Immunome. That remains a huge hole in the story for how we’re going to be able to promote healthy aging. Here, for example, I’m referring to the need to detect the degree of immunosenescence in older adults that poses a vulnerability for cancer and other age-related diseases. With all the new data pouring in for the primacy of the immune system, we need to accelerate ways to get a handle on a person’s immune system status.

That brings me to the recent organ clock paper on the plasma proteomics of healthspan and longevity. In 17-year follow-up of the ~45,000 UK Biobank participants, assessing 8 organs (including heart, kidney, artery, brain, liver, pancreas, lung and immune system). Slow aging of the brain or immune system was linked with the best survival (Figure) and there was also evidence that slow paced aging of both the brain and immune system provided additional benefit beyond each alone.

I hope I’ve convinced you that through a variety of different studies, the brain-immune axis has emerged as more important than previously acknowledged. That’s noteworthy as a root cause of neurodegenerative diseases and for coming up with improved treatments. It’s giving us a great foundation to build on to prevent these diseases in the future and promote healthy aging.

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Thanks to many of you Ground Truth subscribers who helped put SUPER AGERS on the NYT bestseller list for 4 weeks so far. Here’s a new segment I did on PBS about extending healthspan and the new Notebook LM A.I. generated video summary that integrates both the book and Ground Truths for the Secrets of Super Agers!

I’m also very appreciative for your reading and subscribing to Ground Truths.

If you found this interesting PLEASE share it!

That makes the work involved in putting these together especially worthwhile.

Share

All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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.

Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.

To review: a peptide is a short chain of amino acids that is linked by peptide (carboxyl group) bonds after a condensation reaction, removing H2O. The example below is the simplest of just 2 amino acids connected.

In this Ground Truths post I’ll review them by 2 categories: (1) the peptides that have been FDA approved but are getting extensive off-label use; and (2) peptides without FDA approval. Then we’ll get into the implications of the peptide surge.

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FDA-Approved Peptides With Frequent Off-Label Use

In the Table below, I’ve summarized 4 FDA-Approved peptides (one of them is a class, GLP-1s). I’ve previously reviewed the GLP-1 family of peptides extensively (here and here) and it seems every week there is a new potential use case, such as we recently saw for migraine and the one—Alzheimer’s disease— that we await with a very high level of anticipation in September from the 2 large trials with semaglutide. These are one of, if not the most rigorously studied class of peptides ever, with many large, placebo-controlled, randomized trials that followed over the past twenty years from the original GLP-1 drugs such as exenatide, approved by the FDA in 2005. With all the expanding possible indications, the GLP-1 peptides are being prescribed off-label for many purposes, and now people are “microdosing” the drugs despite the lack of data. We recently learned of an elite drug rehab center this is using GLP-1 drugs as the primary method to treat addiction.

There’s a big gap from GLP-1s to the others on the list above , which includes 2 growth-hormone releasing hormone peptides. Sermorelin was previously approved by FDA in 1997 but withdrawn in 2008. So the term “off-label” is off here since it does not have current FDA approval. Nonetheless, it is getting frequently prescribed for increasing muscle mass and putative, unproven, anti-aging benefit. Closely related in Tesamorelin, which is an FDA approved drug for a narrow indication: patients with HIV lipodystrophy. Yet it is being prescribed for healthy individuals to reduce abdominal fat, improve muscle mass and cognitive health. Thymosin Alpha-1 (Zadaxin) is an approved drug for chronic hepatitis B (and hep C outside the US) and during cancer chemotherapy induction. It is being prescribed off-label to rev up a person’s immune system, foster “immune health.” I will get to the adverse effects of these peptides later in the post.

Non Approved FDA Peptides

This is where much of the surge in use of peptides is occurring. The structures of some of the most used peptides are shown below

Below is my summary Table for those and a few additional ones that are getting used. BPC-157 stands for Body Protection Compound-157, derived from a human gastric juice protein. CJC-1295 releases growth hormone, as does Ipamorelin, and these given together may have synergistic (more than additive) effects, which explains why they are frequently provided as a combination. Note the confluence of drugs working on the growth hormone axis in this Table and the one above. There’s also AOD 9604, a growth hormone fragment peptide, being promoted for the same claims. The other peptides, including Epitalon, GHK-Cu, TB-500, Cerebrolysin, Dihexa, and Melanotan II, are summarized below for their presumed mechanism and many purported benefits. The most important column is the last one—there is no evidence from randomized trials in humans that any of these peptides provide the benefits that are advocated. As seen below, two of the peptides have been prohibited by the World Anti-Doping Agency. Collectively, these peptides are being sold under the rubric of “research chemicals” to bypass FDA review. Not shown on the list because they are strictly oral are the collagen peptides which are widely marketed and not-FDA approved.

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NAD+, A Non-Peptide Coenzyme

Nicotinamide adenine dinucleotide (NAD) is not a peptide since the connection between adenine and nicotinamide is not a peptide bond but instead what is known as a glycosidic bond. Despite that, many companies that market NAD+ are calling it NAD+ peptide. It is a natural occurring enzyme in every cell throughout the body that has a pivotal function in energy metabolism (storing and transfer) . The oral preparation are precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NM). A transdermal preparation is now being marketed. They are promoted for “youth repair,” anti-aging, improved cognitive health and energy, even though there are no adequate data to support such claims in people. The main new trend in NAD+ is to get it by injection or infusion.

That trend hit home recently. My wife got a hold of the invitation below to see a property being listed with the perk of getting a free NAD+ shot, “the only anti-aging supplement you will ever need!” (I guess the champagne and light bites weren’t enough). The shots were being provided by a company LIVV that I had not heard of, referred to as a “private health club.”

More on the LIVV health club, a “cutting edge wellness center” that offers an $85,000 premium membership, and recently a lesser alternative of a $10,000 membership initiation fee and $995/month. They’ve got all the peptides and even combinations and some that I haven’t covered above.

Such as kisspeptin (a gonadotrophin releasing hormone analog for reproductive health, promoted for increasing libido) and KPV, lysine-proline-valine, an alpha melanocyte-stimulating hormone, with purported anti-inflammatory and wound healing effects.

You can also see below some special (proprietary) peptides like “LIVV FOREVER.”

It’s not just that any of these peptide preps are unproven, but get a hold of how much an injection costs. Here’s a sampling of the cost per injection of some I’ve reviewed above. I’m certain that LIVV is not alone but likely representative of many other wellness, longevity clinics that are selling peptides and NAD+.

Adverse Effects

They aren’t trivial, well beyond injection site swelling and redness. From the preclinical data for putative benefits there were also important side effects noted. For example, TB-500 was found to accelerate dormant tumor growth and disrupt the immune response in animal experiments. By virtue of inducing broad cell growth, growth hormone related peptides (CJC-1295, Ipamorelin, and Tesamorelin), carry the potential risk of cancer. That theoretical concern also exists for BPC-157 due to its promotion of healing and new blood vessel growth (angiogenesis). Hormonal imbalance may be precipitated by some of the peptides. Across the board, there is no way to know about the right dose, purity, potential contaminants, and the impact of long-term use in people. On the other hand, the adverse events of GLP-1 drugs have been extensively characterized from large randomized trials with placebo controls and, in the United States, from reports derived from 12% of Americans who are currently taking these drugs. Besides the acute phase gastrointestinal effects which may lead to up to 10% of people discontinuing the drugs, there are other potential GI side effects of obstruction, excessive loss of muscle mass, and potentially association with some eye disease adverse events.

Peptide and NAD+ Influencers

While there are many influential voices, the people most associated with promoting peptides, and the ones they are linked with, are summarized in the Table below (generated by Deep Research). Besides those listed, RFK Jr. has strongly advocated BPC-157 and claimed the FDA has suppressed useful peptides. His friend Gary Brecka, who calls himself the Ultimate Human, has backed Sermorelin and the CJC-1295 and Ipamorelin combination.

As for NAD+ injections, there are many celebrity promoters who include Gwyneth Paltrow, Kendall Jenner, Jennifer Aniston, Halle Berry, Joe Rogan, Hailey Bieber, and Justin Bieber.

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Bottom Line

The peptide craze is unfounded. The evidence base for use of these drugs, either for off-label indications or as non-approved drugs, is wanting. There is a chance that peptides besides GLP-1s will eventually be demonstrated to provide health outcome benefits as seen in rodent pre-clinical models. But that has not been established in humans, and there are very limited ongoing clinical trials to illuminate the real efficacy and safety of these peptides.

Why have peptides become so popular without data to support the promotional claims? This, in part, reflects the challenge and mistrust of the medical establishment, which worsened during the Covid pandemic, but was already showing strong signs of opposition by the wide adoption of supplements (with a very similar lack of supportive data on efficacy and safety) long before 2020. Ironically, anti-vax individuals are against shots with as rigorous datasets as we’ve ever seen (e.g. >70,000 participants in the initial mRNA Covid vaccines randomized, double-blind, placebo-controlled trials released in late 2020) but happy to get injections of peptides for which there are scant if any data to support their use. The mistrust is further exacerbated by RFK Jr, the leader of U.S. Health and Human Services, who himself is advocating peptides, stem cells, and other interventions for which data are lacking. The anti-pharma industry position is understandable, with many scandals that have plagued the industry (such as Vioxx, Oxycontin, and several others) without any accountability of the companies or their senior management. No less the exemption of the Covid vaccine manufactures from any liability for adverse effects. But the companies making and promoting these peptides are not especially deserving of blind trust.

There is also a longevity fervor now, with longevity clinics, longevity companies (recently reviewed here), and longevity doctors. When I briefly posted last week about the LIVV company and free NAD+ shots on X, I got backlash from several longevity doctors who prescribe peptides in their medical practice. That wasn’t at all surprising.

When Dax Sheperd recently asked me about peptides in his popular Armchair Expert podcast, I gave him an overview without the details provided in this post. But it was clear that many people in his network, and in L.A., are taking peptides, especially with the list of celebrity influences provided above. Some recent patients of mine have asked if they should be taking peptides, no less physicians in San Diego sending me emails about what’s going on with peptides. While it may be a big thing only in California right now, it is likely to spread across the country with the trifecta of keen interest in wellness/longevity, the powerful effect of influencers, and the revolt against the U.S. medical establishment that is being cultivated.

With the lack of any FDA regulation or oversight of peptides, anyone can get in the business. For instance, I could start promoting BS-2025 and say it has potent anti-aging effects, revs up your immune system, increases muscle mass, libido and sexual function. If you paid $300 per injection each month and heard a celebrity endorsement, the likelihood of you experiencing these benefits would increase. And the doctor who prescribed it would refute the lack of data, saying the absence of evidence is not evidence of absence, and that his patients are deriving substantial benefit without side effects. Then a lab analyzed BS-2025 and found it was an inert placebo and you know what the BS stand for. Unfortunately, this is the potential scenario of peptide marketing and use in such an unregulated environment.

I hope you will find this brief review of the peptide landscape helpful. I remain open to evidence that any one of these peptides or NAD+ will eventually be shown to provide useful health outcome benefits. But that requires proof.

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Thanks to many of you Ground Truth subscribers who helped put SUPER AGERS on the NYT bestseller list for 4 weeks so far. And for the positive feedback on the audio version that I narrated. It took a week to do the recording, but it seems well worth it from your comments.

I’m also appreciative for your reading and subscribing to Ground Truths.

If you found this interesting PLEASE share it!

That makes the work involved in putting these together especially worthwhile.

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All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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.

Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.

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The Tragedy of a Flawed Clinical Trial

Almost exactly 23 years ago, the Women’s Health Initiative (WHI) large, randomized clinical trial of estrogen + progestin vs placebo was abruptly stopped early and the results were trumpeted by the press flagging the “significant increase in the risk invasive breast cancer.” (Front page NYT below)

Soon thereafter, in JAMA, the broader results of the WHI were published and summarized in the graphs below. There was evidence for an increased risk of coronary heart disease, stroke, pulmonary embolism, and invasive breast cancer, and reduced risk of colon cancer and hip fracture. While the increased risk was statistically significant, the absolute risk was small: “the absolute excess risk of events included in the global index was 19 per 10,000 person-years.” For invasive breast cancer, the relative 26% increase translated to an absolute increased risk of 8 cases per 10,000 women per year.

The WHI impact was dramatic and precipitous with more than 60% reduction of hormone replacement therapy (HRT) prescriptions and now, more than two decades later, the adverse results are still inculcated in many practicing physicians.

Why the Interpretation of WHI Was Wrong

The average age of the ~16,000 participants was 63 years, with most more than 10 years postmenopausal (the average age of menopause is ~51 years). Accordingly, these participants were not representative of the women prescribed hormone replacement therapy. That is the major flaw of the study.

The adverse risks were seen with the combination of estrogen and progestin, similar to the trends seen in the preceding, much smaller randomized Heart and Estrogen/progestin Replacement Study HERS trial that enrolled women with a mean age of 67 years. Also, the large UK observational Million Women Study found higher rates of breast cancer.

There was an arm of WHI, a separate randomized trial of estrogen alone (conjugated equine) vs placebo, in over 10,700 postmenopausal women (post-hysterectomy) with very different results shown below, with less invasive breast cancer and no significant increased risk of heart disease or pulmonary embolism. The increased stroke risk was predominantly seen in women age 60-69 years, again highlighting the timing of therapy vs onset of menopause.

Subsequent analyses of the combination estrogen + progestin WHI trial showed when HRT was initiated before age 60 or within 10 years of menopause there was a reduced risk of heart disease and reduced all-cause mortality. This became known as the “healthy endothelium hypothesis.” The route of estrogen therapy also appears to contribute to this drug’s benefit with transdermal administration, bypassing liver metabolism, associated with less pulmonary embolism, deep vein thrombosis and stroke. Currently all of the major organizations, including American College of Obstetricians and Gynecologists, North American Menopause Society (NAMS) support HRT for women under age 60 or within 10 years of onset of menopause. Those 60/10 year cutoffs indicate the perception that timing is critical for avoiding risk and deriving benefit.

Observational data support the potential benefit of early initiation of HRT for preserving cognitive health, reducing the risk of Alzheimer’s disease (a systematic review Figure shown below, the benefit not seen for estrogen + progestin), and less risk for Type 2 diabetes. In aggregate, these diverse salutary effects support an anti-aging impact of estrogen.

In Dr. Lisa Mosconi’s book The Menopause Brain data for estrogen’s protection of cognitive health, brain function, and reduction of brain fog are summarized. Similarly, in the 2024 revised edition of Estrogen Matters, by Drs. Avrum Bluming and Carol Tavris, the protective effects of estrogen for heart disease and cognitive decline are spotlighted (the subtitle sums it up well). A third book, The New Menopause, by Dr. Mary Claire Haver, reinforces these benefits.

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New Studies

In Aging Cell, prescription drugs linked to reduce mortality were assessed in the UK Biobank cohort of over 500,000 participants. As seen in the graph below, among the 9 drugs found to be associated with reduced all-cause mortality, 4 of them were estrogen preparations.

In Lancet Oncology this week, the relationship of hormone therapy to breast cancer was assessed in 13 prospective studies of young women. A total of nearly 460,000 women with a mean age of 42 years were included. Estrogen alone was linked to reduced young-onset breast cancer, while the combination was associated with increased risk of breast cancer. These results are quite consistent with those cited above for the WHI studies.

In Science Advances, the PET scan accumulation of misfolded proteins (Aβ or Tau) in the brain with estrogen replacement (HT) was only significant in older women at baśeline, but reduced in younger women taking HT.

The Organ Clock Pace of Aging Study

The preprint of the study I’m reviewing here was published in Nature Medicine on July 9th without material change. The pioneering organ clock work of Tony-Wyss Coray and his collaborators (see our podcast along with 2 prior Ground Truths noted at the top of this post) culminated in this report of ~3,000 plasma proteins in ~45,000 UK Biobank participants who were followed for about 17 years. The high-throughput protein assay provides biological age data for 11 organs, along with a body-wide age clock (organismal, not organ specific) and conventional (trained on all plasma proteins assessed). The organ age is compared with the individual’s chronological age. Higher organ age was associated with related adverse health outcomes such as heart age for atrial fibrillation and congestive heart failure, and brain age for Alzheimer’s disease. Lifestyle factors also followed suit, such as

smoking with increased lung, brain, and organismal aging. The most important organ clocks related to improved survival were the brain and immune system clocks, as seen in the Figure below (same as Figure 12.5 in SUPER AGERS) The top blue line represents people with slow aging of the brain or immune clock.

With that background of the study, here are the results for estrogen replacement and menopause independent of each other. Estrogen intake was linked to slower aging of the immune system (highest negative magnitude blue bar at left, below) and also the liver and artery clocks. Less prominent in magnitude is the effect on the brain, kidney and lung clocks but all of these were favorable. Note how each organ clock goes in the opposite direction with menopause. In each group partitioned by timing of menopause (N=47), estrogen was linked to a younger immune system age (diagram at right below).

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Synthesis

The protective effect of estrogen largely accounts for why women tend to develop heart disease about 10 years later than men. It’s not just heart disease, there’s immune system dysfunction and decreased bone health that are prominent effects of menopause. One of the most intriguing ways to prolong healthspan in the future is to prevent ovarian failure. When an old mouse gets an ovary transplant from a young mouse, lifespan of the recipient is extended. While we are not able to prolong ovarian life in people yet (perhaps someday), for now estrogen replacement can be considered an attractive alternative.

The WHI stigmatized the use of hormone replacement therapy in postmenopausal women. Cumulatively, in the past two decades since the release of the trial, tens of millions of women soon after menopause missed the potential benefits of estrogen replacement. In my medical practice, I frequently encounter postmenopausal women who have tried to get a prescription for HRT but experienced considerable difficulty or have been unable to do so. This reflects the persistent bias against HRT in the medical community despite the major flaw in WHI and body of evidence that has since accumulated.

Randomized trials are considered the gold standard to assess the impact of a medical intervention. But they are only as good as the hypothesis that is framed. Unwittingly, in the case of WHI, there was indiscriminate enrollment of women, irrespective of time past menopause. Had the hypothesis been that estrogen replacement would provide benefit with the more restricted and current 60/10 recommendations, the intervention would have shined through.

The new organ clock data add to prior reports of estrogen’s effect on preserving bone health, reducing heart disease, preserving cognitive function, reducing the risk of Alzheimer’s disease, and a lower risk of Type 2 diabetes. The Nature Medicine paper provides a new dimension for the benefits of estrogen since it is the first to show the immune system clock is markedly improved. As I reviewed in SUPER AGERS, the immune system appears to be the key to why some people have such extraordinary healthspan. That advantage doesn’t show up in a whole genome sequence but instead requires comprehensive interrogation of our very complex immune system—including assessing the function of various cell types with perturbations and systematic assay of antibodies. The proteomic immune system clock is a promising way to get a handle on this, but more direct means for defining our immunome, which is not available clinically, are in the works (see the First Diagnostic Immunome and Why We Need an Immunome). Moreover, the findings in the new study will need to be replicated by others.

It is surprising that here in 2025 we still have population-level recommendations (i.e. same for all people) without regard to our ability to define the risk at the individual level. If we are concerned about a person’s risk of breast cancer or stroke, a simple inexpensive polygenic risk score could be obtained. Just like the unwillingness to turn the page on the massive WHI miscue, there is the same problem with the medical community reluctance to embrace the use of polygenic risk scores, no less whole genome sequencing. Perhaps someday that resistance will be alleviated.

In closing, the case for estrogen replacement in women after menopause has strengthened. The old adage “timing is everything” certainly applies here, as the last people for whom the benefit would be seen are those who are a decade past onset of menopause. While we haven’t come up with a way to prevent ovarian failure, the totality of evidence supports the use of estrogen to harvest its multiplicity of important health benefits.

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A quick poll for women subscribers

For a deeper look into the topic, I wrote about the organ clocks in SUPER AGERS. The book is available at Amazon for $10.10 right now! That’s ~70% off and I have no idea how long that will last or what prompted it.

Thanks to many of you Ground Truth subscribers who helped put it on the NYT bestseller list 3 weeks in a row. And for the positive feedback on the audio version that I narrated. It took a week to do the recording, but it seems well worth it from your comments.

I’m also appreciative for your reading and subscribing to Ground Truths.

If you found this interesting PLEASE share it!

That makes the work involved in putting these together especially worthwhile.

Share

All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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.

Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.

Subscribe now

Background

To start with I’m going to simplify things because if I tried to diagram all the ways the gut and brain interact bidirectionally, it would be hard to follow. So here is my reductionist representation.

As seen above, there are 4 principal interactions by which the gut influences the brain. There are 2 types of neural pathways, the “second brain” referring to the enteric (gut) nervous system from the cells that line the intestine and communicate to the vagus nerve to the brain (and in the opposite direction, too). There are also connections via the sympathetic, parasympathetic nervous system (autonomic nervous system, ANS) branches and spinal cord innervation to the gut primarily through the ANS.

Cells in the gut produce hormones (enteroendocrine cells) such as glucagon-like peptide (GLP-1), gastric inhibitory peptide (GIP), peptide YY, secretin, gherlin, gastrin, and many others. Some of these regulate pancreatic hormones such as insulin, glucagon and amylin, which can be considered as gut hormones but derived from pancreatic cells rather than intestinal lining cells. The hormonal interaction between gut and brain also goes through the hypothalamus-pituitary-adrenal (HPA) axis.

The abundant and diverse bacteria in the gut microbiome of tens of trillion of cells of more than 3,000 species. These gut bacteria and their metabolites have an outsized impact by producing or stimulating different neurotransmitters (5HT, GABA) and metabolites (e.g. short chain fatty acids, SCFAs) that communicate with the brain and the immune system. For example, see my previous Ground Truths on how a gut bacteria and its metabolites can drive sugar cravings.

The interaction with the immune system is critical to maintain integrity of the gut lining (avoiding “leaky gut syndrome”) and the blood-brain-barrier.

The graphic below does more justice to the complexity of the gut-brain axis compared to what I’ve oversimplified.

New Discoveries and Advances

Inflamed Gut T cells—> Inflamed Brain

The precise way by which the gut can induce inflammation in the brain has remained unclear. In the journal Nature this week it was shown that inflamed gut-derived CD4+ T cells can infiltrate the brain, leading to neuroinflammation and neurological damage in the experimental model. The graphic below shows the intermediate steps and mediators in this process which, in part, involves molecular mimicry, that is to say bacteria derived proteins (antigens) looking like host derived proteins, inciting an immune response.

This was the second of 2 recent discoveries centered around gut-derived immune cells that get into the brain. Newly identified specialized CD4+ T cells from the gut and white adipose tissue establish residence in the brain’s subfornical organ and regulate feeding behavior.

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A Bacterial Protein Blocks Pathogenic Amyloid Formation

Remember the bacterium that Barry Marshall discovered that caused gastric ulcers and was awarded (with Robin Warren) by a Nobel Prize 2005? It was Helicobacter pylori. Well it turns out the H. pylori can do good things too! As in blocking the formation of amyloid protein formation. This week in Science Advances it was demonstrated that H. pylori releases the protein CagA (cytotoxin-associated gene A) which potently inhibits pathogenic amyloid assemblies, via blocking multiple steps (primary nucleation, secondary nucleation, and elongation) for formation in Alzheimer’s disease, Parkinson’s disease and type 2 diabetes. As the authors aptly point out: “Bacteria, often underestimated due to their microscopic scale, offer a vast reservoir of ingenious strategies spanning a myriad of scientific and technological domains” such as the CRISPR genome editing story.

While it remains to be seen whether this discovery in vitro can be translated to a therapeutic, i.e. preventive strategy vs. misfolded proteins, it is certainly worthy of further assessment.

It is notable that this is only one of many recent discoveries for gut microbiome bacteria unexpectedly producing or affecting key biological processes. Like producing sex hormones or playing a critical role in glucose regulation, or metabolites influencing our response to immune checkpoint inhibitors for cancer treatment.

A Plethora of New Gut Hormones

This week there were multiple publications, simultaneous with presentations at the American Diabetes Association annual meeting. Several new gut hormone clinical trials, beyond the ones that are widely used—semaglutide (Ozempic) and tirzepatide (Zepbound, Mounjaro), were unveiled.

Amycretin

There were the randomized trials of subcutaneous (injectable) and oral Amycretin, a molecule that combines a GLP-1 domain with another gut hormone, amylin, as receptor agonists mimicking the natural hormones of both. Below are the results with the pill form for 12 weeks vs placebo for body weight loss. (ETD-estimated treatment difference).

Here is the coverage of the Amycretin results at WSJ

Ecnoglutide

There was a randomized trial of ecnoglutide, a novel GLP-1 receptor, conducted in 36 medical centers in China, with very good results for weight loss as seen below, similar to Amycretin.

CagriSema

There were also 2 Phase 3 triasl reports of the combination of semaglutide and cagrilintide for obesity (shown below) and for obesity plus diabetes.

Beyond these, results for Maritide, a combined GLP-1 agonist and GIP antagonist injectable. given monthly were presented.

Orforglipron

Add to that Orforglipron, a GLP-1 small molecule (non-peptide) pill, which had a favorable effect on hemoglobin A1c in a 40 week trial of Type 2 diabetes. When the preliminary results were announced in April, it was accompanied by this cover of TIME magazine and this article. That may have seemed a stretch for a trial with its primary endpoint of HbA1c reduction. The weight loss achieved (the trial acronym was ACHIEVE) was deemed similar to that of semaglutide, but that isn’t clear from the data below and the trial was not head-to-head. There is an oral semaglutide (Rybelsus) that is approved for Type 2 diabetes and being assessed for obesity. And for Alzheimer’s disease, as discussed below.

Primary endpoint of ACHIEVE

Secondary endpoint of ACHIEVE for weight loss

There were many other new GLP-1 family of drugs and combinations presented without publications in NEJM or The Lancet or are in development. These include the triple receptor drug retatrutide (targets GLP-1, GIP and glucagon), cotadutide, mazdutide, and servodutide (all 3 are combined GLP-1 and glucagon target), and many others.

As I hope you can see, the number of gut hormone drugs has exploded, no less their potential combinations along with the move to oral, small molecule agents. .Through randomized trials, their broad impact has been unequivocally proven for diabetes, obesity, and for treating related conditions of heart failure (with preserved ejection fraction), kidney disease, liver disease, sleep apnea, along with unexpected suppression of addiction to alcohol, cigarette smoking, nail biting and gambling. Add a surprising impact that we’re starting to see for autoimmune diseases.

Even before there is weight loss with these drugs, there is evidence from experimental models of reduced systemic (body-wide) and brain inflammation. What is surprising is that drugs like semaglutide have little direct penetrance to the brain, but exert their effect chiefly through the gut-brain axis. New molecules in this class will have enhanced brain penetrance.

Will They Work For Alzheimer’s Disease?

Meanwhile the most important extension of the benefits of these drugs is for Alzheimer’s disease.

Previously, a Phase 2 randomized trial of an older, less potent GLP-1 drug, Liraglutide in 200 participants, was presented at the 2024 Alzheimer’s Association annual conference but has not yet been published. In participants with mild Alzheimer’s disease after 1 year of treatment there was a reported 18% less cognitive decline and 50% reduced brain shrinkage compared to placebo.

The pending EVOKE and EVOKE Plus trials of daily oral semaglutide participants aged 55–85 years with mild cognitive impairment or mild dementia due to Alzheimer’s disease with confirmed amyloid abnormalities by PET scan or cerebrospinal fluid biomarkers The only difference in the 2 trials is with respect to entry criteria with EVOKE Plus that allows for small vessel pathology. Both trials (study design below), each with ~1840 participants, are expected to be completed (104-week treatment, and there is a 52-week extension) this September with announcement of the results soon thereafter.

I hope you can detect a major weakness in these trials which will reduce the likelihood of their success. The treatment is too late. The participants, with cognitive impairment or dementia are quite far along in the process of brain inflammation, as I recently reviewed. If the trials show efficacy that I’m not expecting (the primary endpoint is the same as used for the approved beta-amyloid monoclonal antibody drugs, change in Clinical Dementia Rating – Sum of Boxes score) that would be great. The right trial would be in people without any cognitive impairment but at high-risk as defined by family history, high polygenic risk score, APOE4 carrier or homozygotes, high levels of p-Tau217 and other blood biomarkers. The other concern about the EVOKE trials is that oral semaglutide is relatively weak compared with tirzepatide (from a head-to-head randomized trial of the injectables), retatrutide, and other molecules, no less the issue of direct brain accessibility.

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Here’s a list of naturally occurring gut-derived hormones that can be mimicked with receptor agonists or antagonists, along or in combination

Concluding Remarks

The extensive work reviewed here has brought the gut-brain axis to the spotlight, just the beginning of a new era of medicine. Even though about 12% of American adults are already taking GLP-1 drugs, that portends a much bigger story ahead. As more evidence mounts for their potent anti-inflammatory effect, especially in the brain, and more pills emerge that reduce the cost, there will be much higher uptake. While it’s not exactly an epiphany or eureka moment, the realization to keep in mind is that the gut talks to the brain and the immune system. We have so many ways now and more in the future to modulate that. In context, we have not had potent ani-inflammatory drugs that exploit the gut-brain axis in the past. Perhaps the old saying, “the way to a man’s heart is through his stomach” will be revised to “ the way to a human’s brain and immune system is through the gut.”

Recall from my prior post on organ clocks that it is our brain and immune system clocks that are most predictive of healthspan and survival (Figure below). If we’re going to extend our healthspan, it will require more attention to preserving the health and slow the aging process for these 2 organs (one is a system).

Our enhanced understanding of the gut-brain axis, and its modulation via GLP-1 drugs, manipulating the gut microbiome and its metabolites (reviewed here), or through neural pathways, holds exceptional promise for a new era of medicine largely unforeseen—that is centered on our gut!

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For a deeper look into the topic, I wrote about the gut-brain axis and a whole chapter on the GLP-1 drugs (which includes the concerns and downsides of these drugs) in SUPER AGERS. Thanks to many of you subscribers who helped put it on the NYT bestseller list 3 weeks in a row. And for the positive feedback on the audio version that I narrated. It took a week to do the recording, but it seems well worth it from your comments.

I’m also appreciative for your reading and subscribing to Ground Truths.

If you found this interesting please share it!

That makes the work involved in putting these together especially worthwhile.

Share

All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.

Subscribe now

1. The proteins from senescent cells predict age-related clinical outcomes

In an elegant study by researchers at the NIH and Johns Hopkins, senescent monocytes were isolated from the blood for more than 1,000 participants in the Baltimore Longitudinal Study of Aging (BLSA). As shown below, the senescent monocytes cells are differentiated by secreting proteins, what is known as SASP for senescence-associated secretory phenotype. The proteins secreted by these monocytes were characterized by mass-spectrometry and compared with body-wide high-throughput proteomics using Somascan (which assayed ~7,000 proteins)from the plasma of the BLSA participants. Over 1500 proteins in common were analyzed using machine learning (LASSO) and shown to predict various clinical traits. These included walk speed, chair to stand pace (and other components of the frailty index), systolic and diastolic blood pressure, fasting glucose, hemoglobin A1c, lipids, inflammation markers of C-reactive protein (CRP) and interleukin-6 (IL-6), DEXA scan results, and waist size. All of this was further validated in another cohort.

While this study does not prove cause and effect relationships, it certainly provides new data on SASP as a biomarker of aging and also highlights the a close relationship with diverse clinical traits and outcomes. Some of the strategies to reverse aging are relying on eradication of senescent cells (known as senolytics) for which the findings in this study may be useful.

2. A new epigenetic age clock connects the dots between aging, the immune system, inflammation and lifestyle factors

Researchers at the Buck Institute for Research on Aging and collaborators published a new DNA methylation clock called DNAm IC, where IC stands for intrinsic capacity, the “sum of an individual’s physical and mental capacities.” The cohort used to construct the clock had over 1,000 individuals aged 20 to 102 years and was then validated in the Framingham Heart Study participants. Here is a schematic of the study:

It outperformed previously validated and widely used epigenetic clocks such as the Horvath and Hannum clocks, and was as good or better than PhenoAge (as shown below, and also GrimAge, not in the Figure) for predicting all-cause mortality.

A higher DNAm IC was linked to lower CD8+ exhausted T cells, higher CD8+ naive T cells, and increased CD28 expression, which relates to T cell activation and proliferation and decreases with age. A high DNAm IC was also correlated with a low iAge, an immune system metric for chronic age-related inflammation. Individuals with high DNAm IC were more physically active, had better cognitive scores, more handgrip strength, consumed more fish and had increased levels of omega-3 fatty acids. High DNAm IC were inversely associated with inflammation markers such as IL-6 and CRP.

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3. People with a fast pace of aging had an increased risk of cognitive impairment, age-related diseases, disability, and mortality

Columbia University researchers published an important study of 2 cohorts, the US Health and Retirement Study (HRS) and the UK English Longitudinal Study of Aging (ELSA). In over a total of 19,000 participants with multiple assessments over more than 10-15 years, which included inflammation makers (CRP and Cystatin), hemoglobin A1c, handgrip strength, balance, walk speed, lung function, and blood pressure.

Shown below is survival related to Pace of Aging at left and the outcomes at right (CIND-cognitively impaired, not demented, ADL-activities of daily living, reflecting disability). The Pace of Aging composite relies on easy to obtain metrics, not using DNA methylation makers, and predicted the outcomes as well or better than the widely used epigenetic clocks known as DunedinPACE of PC Grim Age. Overall, men aged faster than women and the pace of aging picked up in people of advanced age.

4. The Importance of “Immune Resilience” for Healthspan

In Aging Cell, UT San Antonio researchers and collaborators published an analysis for more than 17,500 individuals from multiple cohorts that identified “immune resilience (IR)”—defined as the capacity to resist disease despite aging and inflammation. Their core mechanistic finding was that TCF7, a transcription factor that is vital for T cell function, counters inflammaging and immunosenescence, and is central to healthspan. In the Table below, you can see their finding lines up with all the other studies of gene expression, adjusted for age and sex, whereby the signatures of more inflammaging or immunosenescence align with shorter lifespan, while those with less inflammation or immune system degradation track with longer lifespan.

A Unified Model of I/I

These new studies add to the previous ones that I have reviewed in Ground Truths with organ clocks and high-throughput proteomics. I’ve also gone into much more depth for this topic in my book SUPER AGERS. The totality of evidence supports immunosenescence and inflammaging (I/I) at center stage, the drivers of the 3 major age-related diseases.

The new studies reviewed here, along with several others, lead to a unified model that considers many ways that we can reduce I/I , pulling together evidence from a body of data on lifestyle factors, environmental toxins, the GLP-1 drug effects, and vaccines.

An anti-inflammatory diet that is predominantly plant-based, Mediterranean, low in red meat, and low in ultraprocessed foods, has been closely linked with healthy aging (See my Ground Truths on Optimal Diet). Note that too high a protein intake, particularly from animal sources, promotes inflammation and has been shown to increase atherosclerosis in the experimental model. Also, the important of visceral adiposity, with fat cells producing inflammatory mediators (adipokines) and promoting inflammation fits in this category. The new epigenetic clock study reviewed above was again notable for connecting a healthy diet and DNAm IC.

As reviewed previously, exercise helps maintain the integrity of the immune system and a favorable impact on epigenetic clocks (here and here), all linked to healthy aging. We’ve recently seen how 3 large natural experiments of Shingles vaccines pointed to a 20-25% reduction of dementia, mostly Alzheimer’s, which would be considered to be a breakthrough if this was derived from a drug. Undoubtedly, this has something to do with revving up the immune system in older individuals.

Sleep regularity and quality are critical to promote brain health, reduce neuroinflammation, and this also extends to body-wide inflammation and favorable modulation of the immune system. I recently did a podcast with Matt Walker on this topic which will be posted soon.

Environmental toxins that include air pollution, microplastics and nanoplastics, and forever chemicals, all of which promote inflammation and the age-related diseases. They are presently unchecked and are contributing in the opposite direction of healthy lifestyle factors.

The GLP-1 family of drugs, including semaglutide and tirzepatide, have been shown to reduce body-wide and brain inflammation, both in experimental models and in people even before there is evidence of weight loss. This effect is currently being assessed in 2 large trials of preventing Alzheimer’s disease. Moreover, there are many other gut hormone mimetics (agonists) in the pipeline, which talk to the immune system and the brain, which will be tested independently and in combination, in the future for their potent I/I effects.

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Concluding Remarks

While everything we know generally fits into this model, it is clearly reductionist, oversimplified. In thinking about how the human body works, it’s of course never this straightforward. However, we create models for their usefulness and I believe all of the data over recent years gets us to this synthesis for I/I. There is one problem to highlight. While we’re learning a lot from recent publications, we don’t currently have a way to assess the immune system in people and our markers for inflammation (CRP, IL-6, and cytostatin) are not adequate by themselves. If we’re going to make a push too extend healthspan at the individual level, we will need to have better, practical, inexpensive ways to get at I/I in older adults. I’ve called for the need to have an immunome and better, supplementary inflammation markers, especially now that the evidence for I/I as principal drivers has become so robust.

All of this supports my firm belief that we have an extraordinary opportunity to prevent the major age-related diseases now that was not previously possible. It combines advances made in understanding lifestyle plus factors, multimodal A.I., and new interventions to control I/I. It’s the central premise I advance in SUPER AGERS and why I think we’re at a partially momentous time to make a difference for extend healthspan in the future. That’s without the need for reversing aging, or the unmitigated torrent of pseudoscience from longevity clinics, longevity companies, unproven procedures and total body imaging, and anti-aging supplements, all of which are void of any meaningful data.

The other side note is the sad truth that with the current, profound US defunding of biomedical research we will lose valuable time to pursue this opportunity— to use our I/I enhanced knowledge to extend healthspan and prevent the major diseases. Ironically, primary prevention has enormous economic value and advantage compared to the cost of treatment of any of these age-related diseases. No less the rarity of finding actual cures.

We’re staring at the prevention potential right now, yet stymied from going after it full throttle.

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All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.

One other note of thanks—SUPER AGERS has now been on the New York Times bestseller list for the past 3 weeks, which I’m sure is related to many of you subscribers. So thank you for supporting my work on that project!

These are the first couple of independent reviews that I’ve seen:

WSJ by David Shaywitz gift link

Substack Alex Zhavoronkov link

And, lastly….

Join me for a live chat with Prof Devi Sridhar: https://open.substack.com/live-stream/34109?r=158dl&utm_medium=ios on Tuesday, June 17th 10 AM PST on her new book

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With all the advances in both the science of aging and artificial intelligence (AI), we are in a propitious position to accurately and precisely determine who is at high risk of developing Alzheimer’s disease years before signs of even mild cognitive deficit. It takes at least 20 years for aggregates of misfolded β-amyloid and tau proteins to accumulate in the brain along with neuroinflammation that they incite. This provides a long window of opportunity to get ahead of the pathobiological process, both for prediction and prevention.

A family history of Alzheimer’s and the presence of genetic variants in the APOE4 (apolipoprotein E4) allele indicate an increased risk, as does a polygenic risk score that is based on the combined influence of many genetic variants. However, each of these clues provides little insight about when initial symptoms would likely present. After all, there is a world of difference between whether a person is at risk of manifesting the disease at age 98 instead of 68. Now there are a number of better tools that have sharpened our predictive capacity. At the body-wide level, measuring the degree of DNA methylation can serve as a kind of clock, indicating whether biological age is outpacing chronological age—a predictor of dementia. Fast-paced aging measures by eight so-called organ clocks, including ones for the brain and immune system, have been shown to predict adverse health outcomes, including Alzheimer’s disease.

Beyond the hundreds of plasma proteins that can serve as a brain clock, there are specific blood-based protein biomarkers. An assay that measures the amount of a misfolded protein called p-tau217 (tau phosphorylated at threonine-217) accurately differentiates Alzheimer’s from other forms of dementia. [I wrote about this breakthrough test in a previous Ground Truths.] Although several other blood biomarkers have been reported, p-tau217 is the earliest to increase in the long course of disease development and has consistently excelled in the accuracy and specificity of its predictions. It has been shown to be as good as or superior to p-tau217 assessed from cerebrospinal fluid, which requires a lumbar puncture, and as accurate as a positron emission tomography (PET) tau scan. The Figure below shows it to be the best of all comparative plasma biomarkers. Furthermore, this biomarker provides a temporal window for flagging the risk of the disease multiple years in advance. Other protein markers have also been correlated with risk (including p-tau181, microtubule-binding region containing residue 243, glial fibrillary acid protein, neurofilament light chain, and plasma proteins such as growth differentiation factor 15). A group of these could be used in a panel to back up the finding of p-tau217. While p-tau217 has been available at LabCorp and Quest, among other labs, for the past 2 years, one test from the Japanese company Fujirebio (measuring levels of p-tau 217 and beta-amyloid 1-42) was cleared by the FDA to facilitate diagnosis in patients with symptoms. By report, 92% of individuals with positive blood-test results had the presence of amyloid plaques confirmed by either a PET scan or a spinal-fluid test, while 97% of individuals with negative results from the blood test also had confirmed negative results using the other methods

A new study of a cohort of 400 middle-aged participants with intact cognitive function and extended follow-up for Alzheimer’s disease again showed the accuracy of p-tau217 and its ratio p-tau217/Aβ42 for discriminating PET Aβ scan status.

A new paper in Nature Aging assessed nearly 7,000 unique plasma proteins (Somascan, see prior Ground Truths on high-throughput plasma proteins and A.I.) in ~1,300 participants with Alzheimer’s and ~2,100 who were cognitively intact. The analysis using machine learning identified several proteins that predicted clinical AD and biomarker AD status.

Again the value of a plasma p-tau217 test compared with cerebrospinal fluid or amyloid PET scan was confirmed.

On another front, AI offers the possibility of predicting Alzheimer’s with retinal images from a photograph or by optical computed tomography. When analyzed by deep learning AI, the images can forecast the risk of Alzheimer’s in the next 5 years among people who are asymptomatic. Moreover, layers of data from brain clocks, biomarkers, and other tests can be integrated in a multimodal AI model to determine whether a person is at high risk of Alzheimer’s and, if so, project a timeline for the disease’s progression.

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Once an individual has been accurately identified as having a high risk for Alzheimer’s, there are now many means of prevention, or at the least, substantial deferral. Lifestyle factors, such as exercise, have been demonstrated to substantially lower p-tau217, which may signify a preventive strategy akin to lowering low-density lipoprotein (LDL) cholesterol for prevention of heart disease. In a recent study following more than 100,000 participants for 30 years, only 9% reached age 70 without chronic diseases, including Alzheimer’s. Their diet was rich in fruits, vegetables, and grains and low in red meat, and otherwise Mediterranean-like. A recent randomized trial of participants with elevated p-tau217 and other biomarkers indicated that lifestyle improvements including a healthy diet, loss of weight, and exercise lowered risk. Multiple studies have emphasized the importance of healthy sleep habits, including the amount of deep sleep, when clearance of the brain’s metabolic waste products occurs.

The recent Lancet Commission on dementia concluded that about 70% of cases are caused by Alzheimer’s disease, and that 45% of them are preventable. The strategies for prevention, beyond lifestyle factors involved with p-tau217 reduction, include management of hypertension, diabetes, high cholesterol, and obesity, as well as treatment for hearing and vision loss, avoidance of excessive alcohol, reduction of intake of ultraprocessed foods, and cessation of smoking.

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Recently, three impressive natural experiments—observational studies of naturally occurring, real-world events—all pointed to the role of shingles vaccination in protection from dementia [Reviewed here]. Other observational studies have also indicated that influenza vaccines can protect against Alzheimer’s disease. Although these findings do not provide any proof of a viral basis for Alzheimer’s, they do support the notion that revving up the immune system may help stave off the disease.

When a person is identified at high risk for Alzheimer’s, aggressive surveillance can be undertaken using the same baseline assessments that established risk. That includes further tests involving the brain organ clock, AI analysis of the retina, p-tau217 and other biomarkers, and, if necessary, brain imaging with either magnetic resonance imaging (MRI) or PET.

Multiple observational studies have indicated a reduction of risk for Azheimer’s with the use of GLP-1 (glucagon peptide-1) drugs, which are now being tested in randomized trials. If they pan out, this may be because of their strong anti-inflammatory effects in the brain. A new experimental model study demonstrated a GLP-1 drug favorable effect of less cognitive decline by restoring cellular energy metabolism and improving microglial phagocytosis (schematic below)

Besides the interventions reviewed above, considerable work is ongoing to manipulate the gut microbiome. Studies in which gut microorganisms are transplanted from both people with Alzheimer’s disease and control subjects to young heathy rats indicate that the composition of the gut microbiome is a risk marker for the disease. Also in the pipeline for prevention of Alzheimer’s disease in people at high risk are potent oral medications with high penetrance to the brain, such as one that targets NLRP3, a protein involved in inflammation.

With all of these innovations, there has never been a greater opportunity to identify individuals at high risk for Alzheimer’s and prevent them from developing the disease, an overall strategy that would be far preferable to trying to cure or treat it once cognitive impairment has already begun.

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BTW, I have a chapter in my book SUPER AGERS that gets into much more depth for how we can use the p-tau 217 blood biomarker along with all of a person’s layers of data to go into aggressive prevent mode. I want to thank many of you subscribers of this newsletter who have helped put it on the NYT bestseller list and the top non-fiction new release book on Amazon.

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All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.

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What Is CRISPR 1.0?

This is the type of genome editing that led to regulatory approvals for sickle cell disease and beta-thalassemia in late 2023, after a decade or research. It relies on making a double-strand break in DNA, as shown below, cutting it into 2 pieces. When that occurs the cell wants to repair the chromosome broken ends. But that leaves a small percentage of mistakes in the repair process of rejoining. The Cas 9 nuclease keeps cutting and more mistakes accumulate. Ultimately, the gene is disrupted when Cas9 can no longer recognize the mistake-laden sequence pf insertions and deletions. This is a disruptive knockout strategy that doesn’t fix a gene. That works for sickle cell disease and beta-thalassemia because the disruption targets a gene called BCL11A (that turns off fetal hemoglobin production) to restore fetal hemoglobin production instead of actually fixing the defect in the hemoglobin gene. The editing is done ex vivo—outside the patient’s body.

That lack of fixing also sets the stage for a very complicated treatment course. The individual has to undergo a collection process of blood-producing stem cells that requires being connected to an apharesis machine for several hours, getting multiple transfusions, then chemotherapy to wipe out the bone marrow. This leads to a precipitous drop in white blood cells and requires hospitalization for weeks or months, under sterile conditions. Ultimately, the edited blood stem cells are infused but the patients is stuck in the hospital until the immune system recovers. Sounds grueling, very expensive, and complicated? Yes, it sure is.

Moving Forward with CRISPR 2.0

Instead of a double-strand break, base editing (pioneered by David Liu and colleagues, and discussed in our podcast) creates a single-strand nick (Figure below from Wang et al) and sets up a precise single base pair substitution, such as changing A's into G's G's into A's T's into C's or C's into T's. This constitutes directly fixing of the defect by doing chemistry of an individual’s DNA base.

Base editors were used in the new report, as we’ll get into. They are great for certain single base pair substations, but not all. There is another methodology called prime editing that is more versatile, capable of changing an A to a T or insertions of multiple missing letters like CTT, the most common genomic basis for cystic fibrosis. It is regarded as CRISPR 3.0. For more depth on the different editors, this is a very good review paper in Cell.

The first case of base editing that received much attention was done on T cells ex vivo for a 13-year-old girl with leukemia. Base editors have also been used in the body (in vivo) for familial hypercholesterolemia (but not individualized by the recipient’s genomics) and more recently (March 2025) for alpha-1 antitrypsin deficiency. A different approach from base editing (called ARCUS, which uses a viral vector for delivery) was used for another urea cycle disorder.

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The New Report

This was unique in many respects. KJ Muldoon was born in August 2024 with lethargy, rigid muscles and other worrisome symptoms. Genome sequencing revealed this was due to a severe urea-cycle disorder that leads to accumulation of ammonia and death in about half of infants affected, and short of death, the high levels of ammonia cause lethargy, seizures, coma, and brain damage. The disease-causing gene was CPS1 (carbamoyl-phosphate synthetase 1 deficiency), a 1 in a 1.3 million births genetic (ultra-rare) disease. KJ was hospitalized and awaited a liver transplant, listed at 5 month of age, if a donor organ became available. In the meantime, therapy consisted of a low protein diet and ammonia lowering (“nitrogen scavenger”) medications.

To get to the basis of KJ’s genomic defect and attempt a cure, the team at Children’s Hospital of Philadelphia (CHOP) and Penn Medicine (led by Drs. Rebecca Ahrens-Nicklas and Kiran Musunuru) sequenced KJ and his parents. The father had a truncating CSP1 variant (Q335X) and the mother a different variant, E714X). They developed an adenosine base editor (called K-abe, schematic below) to specifically correct KJ’s defective CPS1 gene. The approach taken was particularly rigorous and comprehensive. Within 6 months they tested the editor in cells with the genomic variants, in mice (bred to specifically have KJ’s CPS1 mutation), in non-human primates, and got FDA approval to give it. It was administered intravenously using delivery via mRNA + nanoparticles beginning in February 2025 and then with 2 subsequent doses. The base editor used was directed against the paternal mutation (a G→A stop variant) at the Q335X site of the CSP1 gene.

Dosing started at ultra-low and the first showed little efficacy as reflected by plasma ammonia levels. The second dose was ~3 weeks later and the third dose (not reported in the NEJM paper) was in April, just ~2 weeks ago. These showed signs of clinical benefit (vida infra).

The compressed timeline for achieving all this work was unprecedented!

What is missing to date is a liver biopsy, due to risk to the infant, to prove the targeted CSP1 editing. There is also lacking evidence of a cure—”just” a reduced need for medications and the restrictive diet. But also encouraging is that KJ is now reaching developmental milestones and although he sustained two viral infections, both were without an ammonia crisis. Further doses of the base editor can be administered with the mRNA approach (rather than a virus vector that can induce an immune response). Regarding uncertainties, we also don’t know about the durability of the editing, any mosaicism impact (only some liver cells edited), and the potential of any off-target effects (rigorously assessed in the 6-months sprint of lab experiments but not yet in KJ).

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Concluding Remarks

This case of KJ represents a human first—-personalized, N-of-1 genomic intervention with base editing (CRISPR 2.0), in the body (in vivo), to directly fix a pathogenic (disease-causing) gene mutation. This bespoke intervention was accomplished in a remarkably compressed timeline that included rigorous assessment in cell and animal models, along with regulatory approval to proceed. It embodies something in medicine we have not and could not have done previously. It involved a dedicated team at CHOP and Penn and collaborators spread out around the world.

There are many specific aspects of the case that deserve attention. The fact that this work culminated from many years of NIH supported research, including the current report, at a time when we’re seeing profound and indiscriminate cutting of such funds

Related to that is the use of the mRNA-nanoparticle package for delivery of the intervention that is also being subject to cuts in funding at NIH without basis, no less potential lack of support by FDA, tied into misguided concerns about the Covid shots that saved the lives of over 30 million people. The mRNA delivery platform is also being used for developing vaccines for infectious pathogens for which there is no vaccine, for the genome editing programs, for cancer vaccines that have been successful for treating intractable cancers (neoantigen vaccines for both pancreatic cancer and renal cell carcinoma have been reported with a striking reponse in a limited number of patients).

We don’t know the actual cost of KJ’s genome editing, but had he gone onto a liver transplant it would likely have exceeded what this project cumulatively cost, and was supported by in kind contributions from multiple companies including Danaher, Aldevron Biosciences, Acuitas Therapeutics, and Integrated DNA Technologies.

The most important takeaway is that we have a new way of approaching rare disease with base and prime editors which account for ~90% of disease causing genetic mutations. Recall that there are about 10 thousand genetic rare diseases affecting ~6% of the world’s population, or about 400 million people. The overall global burden of rare and ultra-rare genetic diseases is huge, Were the approach pioneered in this case report made scalable, less expensive, and practical, imagine how many people could benefit.

Indeed, we are likely to see such scalability in the future. Many of the steps along the way here could be streamlined, some even omitted, such that this case be considered a template for the future. While today we can only approach diseases based in the liver, and potentially by intrathecal delivery into the brain, or outside the body editing T cells (or other cells), there is arduous work to improve the breadth of in vivo delivery to other vital organs. The Innovative Genomics Institute at UC Berkeley is orchestrating such streamlining efforts along with expanding targets to the lung, muscle and spine (the latter to achieve control of pain). Genomic editing in utero has also started.

There is another reason that this case is so important. Many rare diseases share common threads with common diseases. In my new book SUPER AGERS, which hit the NYT bestseller list this week, I explain how fixing the rare genetic defect of familial hypercholesterolemia with base editing, which is being undertaken by Verve Therapeutics, could be the basis of a one-shot treatment to prevent heart disease someday in the future. There is already preliminary work ongoing for prevention of Alzheimer’s disease with gene therapy of the APOE allele in people with two copies of APOE4, carrying a very high risk for the disease. And there are many other examples for how such advances for a rare disease could ultimately transform our approaches for important common diseases. It will take time, but I hope this post transmits the promise and excitement that lies ahead.

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All content on Ground Truths— newsletters, analyses, and podcasts—is free, open-access.

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. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.

—The Breakthrough Test for Alzheimer’s

—Our Diet and Healthy Aging

—The Business of Promoting Longevity and Healthspan

—Our Sleep, Brain Aging, and Waste Clearance

—What Can 11,000 Proteins in Our Blood Tell Us

—The Emergence of Protein Organ Clocks

—Exercise May Be the Single Most Potent Medical Intervention Ever Known

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As I wrote in Science last year, our ability to do accurate medical forecasting at the individual level is about to take off. While much of the science of aging is focused on reversing aging, the part that has not adequately acknowledged is our newfound capability to precisely and accurately measure the process in a person, not just body-wide (a molecular clock that quantifies the gap between a person’s chronological age vs biological age) but also at the organ level (see the protein organ clocks link above), and temporally (number of years in advance before symptoms develop).

While there are many shots on goal to reverse aging (such as cellular reprogramming, senolytics, rapamycin, rejuvenation of the thymus gland, NAD+, etc), none are proven in people and all carry some risk. In contrast, we have many ways now to prevent the major 3 age-related diseases—cancer, cardiovascular, neurodegenerative. One example, organ clocks for the brain, heart and immune system, will be essential to help guide the way. As you can see from the links at the top of the post, lifestyle factors of diet, sleep and exercise play a critical role in (and there’s much more to that!).

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Here’s a gift link to my op-ed in the New York Times today that is a preview to my SUPER AGERS book coming out in 2 weeks.

The full text with some links is below, fact-checked by NYT (which is far more extensive than what is done for medical journal articles)

The dream of reversing aging has captivated humans for centuries, and today science is closer than it ever has been to achieving that goal. Which is to say: It’s still pretty far away.

That’s not for lack of trying. Some researchers are attempting to reprogram cells to make them biologically younger, which has been shown to reverse features of aging in older animals. Unfortunately, this can also induce cancer. Other researchers are studying drugs called senolytics, which aim to clear aging cells out of the body. However, they can also destroy other cells humans need to survive.

Transfusions of blood from young mice appear to rejuvenate older mice, but companies offering this unproven treatment for humans are charging a lot for a potentially dangerous therapy. And while some longevity enthusiasts are taking the drug rapamycin because studies have shown it helps animals live longer, it also weakens the immune system and hasn’t been proved to work in people.

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I find these efforts intriguing and worth pursuing. But most people don’t simply want to live until 110. They want to extend the amount of time they live free of serious disease, a concept known as health span. That’s why the most sensible approach is to reduce the toll of three major age-related diseases: cancer, heart disease and neurodegenerative disorders, such as Alzheimer’s disease. It may be less flashy, but it’s more attainable than ever.

It’s estimated that at least 80 percent of cardiovascular disease cases, 40 percent of cancer cases and 45 percent of Alzheimer’s cases are preventable. Even with a long lag — these diseases can each take 20 years or more to develop — researchers have struggled to accurately define a person’s risk early enough to intervene effectively. Sure, someone can take a genetic test and learn he’s at a heightened risk for Alzheimer’s disease, but what good is that if he doesn’t know whether the disease will emerge early, when he’s 95 or not at all?

In the near future, doctors may not only be able to identify whether a person is at high risk for a serious, age-related disease, they may also be able to predict when that disease is most likely to manifest and how quickly it could progress. Several recent discoveries from the science of aging are making this increasingly possible.

Since the 2000s, scientists have used a person’s genetic sequence to calculate his inherited risk for certain diseases. In just the past five years, the amount of data the medical field can glean about a person’s health on top of that has ballooned. Beyond traditional tools such as medical records, routine lab results and imaging, doctors can draw from a range of biological clocks that help track how the body is aging.

For example, scientists can now measure thousands of proteins from a single vial of blood to generate what are called proteomic organ clocks. These recently discovered clocks can estimate the pace of aging for the brain, heart, liver, kidneys and immune system. These clocks can reveal, for instance, if a person’s heart is aging faster than the rest of her body — like a car mechanic discovering everything is working as it should, except for the rear brakes. Other molecular clocks can calculate a person’s biological age compared to his chronological age. The most rigorously studied one is the so-called epigenetic clock — a reading of parts of our DNA that can be taken from a saliva sample. New blood tests can also detect early signs of the three major diseases linked to aging.

Layering all of this biological information with recent advances in artificial intelligence allows health providers to make increasingly sophisticated predictions about a person’s likelihood of developing a disease.

Take a person who wants to determine her risk of Alzheimer’s disease. She can now undergo a blood test for a protein that quantifies plaque buildup in the brain that’s associated with the disease. Soon a doctor might also use a proteomic organ clock to assess whether her brain appears to be aging faster than the rest of her body or analyze a photo of her retina, an emerging tool that, when combined with A.I., can help estimate the likelihood of developing Alzheimer’s disease in the next five to seven years. There are similar tests that can be done to assess cancer and heart disease risk.

This level of insight can usher in a new way to approach such diseases: active surveillance paired with aggressive lifestyle changes. A person deemed at high risk for Alzheimer’s might undergo regular assessments and brain imaging while also taking preventive steps to lower her risk. That could include cutting back on ultra-processed foods, increasing physical activity and addressing any changes to hearing or vision loss — factors that can influence cognitive decline. Doctors could also recommend prioritizing sleep, reducing alcohol and social isolation or getting the shingles vaccine, which has recently been shown to reduce dementia risk. Some might also consider taking GLP-1s, diabetes and weight loss drugs, which appear to reduce harmful inflammation in the brain and body and are being tested in clinical trials to prevent Alzheimer’s.

Pulling together this medical information and turning it into individual plans for preventing chronic diseases is different from today’s approach. Cancer screening protocols, for instance, rely largely on a person’s age. This is also where A.I. models can best benefit medicine. These models are improving in accuracy and reasoning and could one day incorporate data from our gut microbiomes or immune systems to make disease predictions even more precise.

Getting this right will require further study and investment. We don’t want to exacerbate health inequalities by making this kind of medical care accessible only to a wealthy few. The Trump administration’s major reductions in governmental support of medical research will dim these prospects.

Getting an injection of youthful blood or taking the latest trendy anti-aging supplement might seem like a shortcut to a longer life. But extending the years people live without the burden of major age-related diseases is what should be a national priority.

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Here’s a Figure from the book mapping out the strategy for Alzheimer’s

A Quick Poll

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As you can imagine, I’m excited to get my new book out. I've worked with my publisher, Simon & Schuster, to share an exclusive offer just for Ground Truths subscribers. Through May 5, you can pre-order a hardcover copy of the book at Bookshop.org and get 15% off with code SUPERAGERS15. It’s notable that Bookshop.org supports independent bookstores across the country. Of course there’s also Amazon which currently offers a discount on the book, but it’s certainly not helping these bookstores.

In this post, I’ve only scratched the surface about the content of the book. Here’s the back cover to give you an idea of what some people had to say about it.

Thanks for reading and subscribing to Ground Truths.

If you found this interesting please share it!

That makes the work involved in putting these together especially worthwhile.

Share

All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.

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. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.