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Science should guide Florida’s pesticide conversations
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Your Thymus and Your Healthspan
Our thymus gland plays a central role in the development or our immune system, specifically for supporting T cell development (how these cells got their name, maturation and differentiation in the thymus) and discriminating between self and foreign, non-self antigen proteins with production of dendritic cells. As we age, our thymus gland shrinks—the process known as involution—with progressive change from spongy to fatty tissue, with loss of functionality. But this process, with respect to timeline and extent, markedly varies from one person to the next. And to make things even more complicated, our thymus gland anatomy and precise location in the chest also is highly variable. So the famous Frank Netter diagrams from the 1960s (such as at left below) don’t capture the remarkable heterogeneity that a random set of 12 chest CT scans (below at right). What I consider as 2 landmark papers in Nature this week (here and here) used AI to quantify health of the thymus in 2 large cohorts, and then correlate the metric to a broad array of health outcomes. In this edition of Ground Truths, I’m going to cover three questions: (1) How was thymus health determined by AI?; (2) How is thymus health linked to key clinical outcomes? and (3) Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? Subscribe 1. How was thymus health determined by AI? This was accomplished by extensive work developing and validating an AI pipeline for 2 stages, the first for localization and segmentation of the thymus bed, and the second to quantify a digital marker, termed the thymic health score. There’s a lot to this algorithmic development, so I won’t go into all the details, but just provide a rudimentary outline of what was done. The 1st stage used supervised learning with 2 radiologists reviewing 2,461 chest CT scans. That work trained a 3D U-Net model to automatically identify the thymic bed’s 3D cropped region using center of mass coordinates, which reached 99.8% accuracy. The 2nd stage used a foundation model that was pre-trained with SwAV (which stands for Swapping Assignment between multiple Views), a self-supervised model, that generated a high-dimensional thymus representation of 4,096 features. That compares to the radiology reductionist and subjective scoring of 0 to 3 where 0 means the thymus is fully degenerated and fatty, and 3 is considered dense, intact glandular soft tissue. Notably, the self-supervised learning (SSL) performance was superior to supervised (AUC ~0.75 vs 0.55, respectively) reflecting the shallowness of the 0-3 classifier vs SSL’s holistic, self-taught AI. The thymic health score ranged from 0 to 100, with the highest number indexed to fully preserved thymic health. The algorithmic work extended to explainability with both Shapely value distribution, meaning the model was holistic not relying on any “magic” pixel, and occlusion sensitivity, demonstrating the model’s performance was not affected by ribs, sternum, lung tissue, but rather focused on the thymic bed directly. Below are a few saliency maps from the occlusion sensitivity that indicate the thymic bed focus, not affected by neighboring structures, using the jet color scale. Now the AI was ready for processing ~25,000 CT scans, each over 30 MB files, from the 2 large participant cohorts to provide a thymic health score, it did so in less than 14 hours, which is less than 2 seconds per scan! Share 2. How is thymus health linked to key clinical outcomes? The two cohorts were the National Lung Screening Trial, NLST (N=25,031) and the Framingham Heart Study, FHS (N=2,581) each with baseline demographics and long term follow up of >12 years for health outcomes. From the NSLT, you can see below that increased age and body-mass index were correlated to reduced thymic health. And, overall, men had reduced thymic health scores compared with women. There are a lot of graphs in the paper for outcomes, for both the NLST and FHS cohorts. To simplify the major outcomes, below is a composite Figure with striking reduction of all-cause mortality and for the different causes of death. The results were consistent between the 2 cohorts. For example, the cardiovascular mortality hazard ratio average was 0.57 in NLST and 0.38 in FHS (weighted to be 0.53 for the aggregate). The reduction of mortality also extended to digestive diseases and pulmonary disease (data not shown below). Lung cancer incidence was reduced by 36% for high vs low thymic health (Figure below, with a panel -incidence and b panel-mortality, adjusted for age, sex, BMI, smoking status). Notably, there was a smoker’s paradox: lower incidence and improved survival for lung cancer in smokers who had a high thymus health score. Smoking was associated with lower thymic scores whereas alcohol was not. Higher thymic health was linked to higher HDL cholesterol, lower triglycerides, lower fasting blood glucose, and lower systolic and diastolic blood pressure. Inflammation biomarkers, such as C-reactive protein and interleukin-6, were elevated in the people with lower thymic health scores. In their second paper, the same team looked at the relationship between thymic score and outcomes for 3,476 patients receiving cancer immunotherapy. The non-small cell lung cancer progression-free survival was reduced in patients with low thymic health score. A parallel relationship for survival was seen for other types of cancer including melanoma, breast, and kidney with a 44% lower risk among high thymic scores (Figure). A similar pattern was seen with different immune checkpoint inhibitors. The thymus health score outperformed programmed death ligand-1 (PD-L1)and tumor mutation burden (TMB) assay of the tumor and was an independent prognostic marker of progression-free survival. In this dataset, a direct connect with thymus score and adaptive immune function was noted with a correlation before cancer treatment for both T-cell diversity and thymus T-cell production (a metric known as T cell receptor excision circles). Thymus Removal Study There is a highly relevant citation about thymus function before moving onto ways to rejuvenate it. In 2023, a very important study of thymus removal during cardiothoracic surgery was published, with 1146 patients undergoing thymus removal vs 1146 matched controls (mean age 55 years). The adverse outcomes for thymus removal were striking, with a 2.9 higher risk of all-cause mortality and doubling of cancer incidence, 1.5 fold increase in cancer mortality, and 1.5-fold increase in autoimmune diseases. The immune function showed marked compromise after thymus removal, as reflected by CD4+ and CD8+ T cells (Figure below) Share Ground Truths 3. Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? In recent months we’ve learned a lot about the process of thymus involution and the pathways by which this may be modulated. Thymus involution is primarily due to loss to thymus epithelial cells (TECs) and there are 2 subtypes with different functions: the cortical, responsible for positive selection of T cells, and the medullary, for negative selection. When adipose tissue infiltrates the thymus, thymic adipocytes are pro-inflammatory, knocking out T-cell output. Likewise, systemic inflammation, or “inflammaging,” from smoking, obesity, and chronic stress promote thymic adipocytes. Now, from preclinical studies, we know about key pathways that account for these processes. Historically, back in 2014, FOXN1 was recognized as a single master transcription factor essential for TEC function, with studies in mice with forced FOXN1 upregulation leading to thymus regeneration. That laid the foundation for potential regrowth of quiescent thymus cells. It took awhile to find pathways to accomplish this goal and to even refute its role as the master regulator. The Liver-Thymus Axis Feng Zhang and his team recently showed that injection of an mRNA vaccine to the liver encoding DLL1, IL-7 and FLT3-L in combination, factors known to support thymopoiesis (Figure), successfully enhanced immune function in aged mice. However, the effect was transient. The FGF21 Story Two reports in 2025 addressed the thymus gland’s production of FGF21, a growth factor (fibroblast growth factor 21) and its control of thymus involution. This growth factor is also produced by the liver, but it doesn’t have impact on the thymus in aged rodent models. In contrast, The liver’s hepatocyte growth factor (HGF) has been shown to reverse senescent TEC structural changes. Growth hormone stimulates production of insulin growth factor-1 (IGF-1) in the liver and the thymus. Two small studies in human participants (TRIIM, for Thymus Regeneration, Immunorestoration, and Insulin Mitigation) of 6 and 50 people, respectively, treated with combined human growth hormone, metformin and DHEA, suggested the potential of slowing epigenetic aging and improving thymus mass and function. But the combination of drugs, small sample, and lack of controls make conclusions murky. Increased thymus FGF21 led to increased CD8 T cells in old mice and extended healthspan and improved physical performance. Building on the previous FOXN1 data, ablation of β-klotho, the obligatory co-receptor for FOXN1, accelerated thymic aging. The benefit to FGF21 was confirmed in a companion paper using an FGF21 knock-in mouse model showing thymus enlargement and increased TECs throughout the lifespan. (schematic Figure below). The accompanying editorial for these 2 papers speculated: “The proposed link between age-associated thymus involution and organismal aging is intriguing, and suggests we might seek to achieve systemic rejuvenation by counteracting thymic involution.” Other Factors Lessons from the Axolotl (Mexican Salamander) In an elegant set of experiments of the axolotl (Figure), known for its complete thymus regeneration after total surgical removal, mediators were identified. Surprisingly FOXN1 was dispensable. But midkine, a growth factor, appeared to be the driver, the initiator of thymus cell growth, survival, and repair. Other components that contributed were Postn+ (periostin-expressing mesenchymal niches) and Ccl19, a chemokine protein from the bloodstream. RANK and RANKL RANK (receptor activator of nuclear factor κB its ligand (RANKL) have been considered key regulators of medullary TECs. In a study of both aged mice and human thymus cell cultures, their key role was confirmed, with multiple benefits of resorting TEC function, recruitment of progenitor cells, and T cell development. Subscribe Summing Up This body of work strongly supports the health of the thymus gland as a critical regulator of human healthspan, not just a correlate or link. The new landmark studies are reinforced by the regenerative biology experimental models that have shown, via an array of mediators, that healthspan of aged mice is at least in part dependent on thymus gland function and its critical role for maintaining adaptive immunity. It sure seems that we’d be better off having an immune reservoir of naive T cells instead of a profile in older adults of exhausted, low quality, memory T cells, with a senescent phenotype. It is striking that we ignored the importance of the thymus gland for many decades. A wake-up call was the results of the thymectomy matched control study reviewed here, with the opposite of high thymic health score improved health outcomes. The convergence of AI and healthspan here is notable. The exceptional and laborious work for developing and validating (no less explaining) the AI to quantify thymus health set the foundation for probing the connect the major health outcomes in two cohorts with extensive follow-up. We’ve never had a way to meaningfully quantify the thymus gland before, so this represents important leverage of supervised, self-supervised, and transformer models. The study wouldn’t have been possible without AI. And it begs the question as to whether there are ways we can maintain our thymus at a high health score. But it’s not so simple to rejuvenate our thymus. There are multiple risks including the induction of autoimmunity, increasing the risk of cancer, and inducing a pro-inflammatory state. For example, factors that increase TEC proliferation could compromise the medulllary negative selection process and leak out auto-reactive (self-attacking) T cells. Thymic cells could be induced to proliferate, but we know, for example, that growth hormone and IGF-1 are associated with an increase risk of cancer. If thymus rejuvenation doesn’t clear out the accumulated senescent cells in older adults, then inflammation within the gland could block the production of TECs. Keeping these risks in mind, we now have identified many ways to keep our thymus healthy as we age that undoubtedly will be tested in clinical trials going forward. Ultimately, the benefit-to-risk tradeoffs will be defined. In the meantime, we have desperately needed an immunome. As I’ve stressed in multiple prior Ground Truths, we have no test in the clinic to assess a patient’s immune status! It was very encouraging for me to get an email from Hugo Aerts, the senior author of the landmark papers in the days after they were published: “I also wanted to say that your Substack on “Why We Need an Immunome” was inspiring for this work. We found it a very compelling perspective and greatly enjoyed reading it.” Just having an assessment of a person’s immune status via a chest CT scan, with millions of these performed per year, might help in guiding the right immunotherapy for cancer (e.g. more intensive, combinations for those with low thymic health scores) and help define people who are increased risk for age-related diseases of cancer, cardiovascular, and neurodegenerative. The main theme of Super Agers is that we now have many layers of data (genetics, proteins, biomarkers, organ clocks that can be integrated via multimodal AI) for us to define a person’s specific risk decades before one of these age-related diseases leads to symptoms, enabling prevention. From the new studies this week, we can add thymus health score as yet another way to understand a person’s risk, a window into their adaptive immune system and healthspan. And perhaps someday we will be able to safely rejuvenate the thymus, or maintain its health through one’s life, and use the thymus health score to monitor. NB: I wrote this post (No A.I.) A Quick Poll Loading... ********************************************************************* Thanks to Ground Truths subscribers (now > 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Share Ground Truths Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Leave a comment Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. 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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Investment and Statecraft: The International Politics of Sovereign Wealth Funds - Georgetown Journal of International Affairs
In 1953, Kuwait established the world’s first sovereign wealth fund to invest the country’s oil revenues and generate returns that would reduce its reliance on a single resource. Since then, over 100 separate funds have been created to preserve national wealth and ensure long-term fiscal sustainability. Today, they manage over $10 trillion in global assets. In this discussion with GJIA, political economist Kathryn Lavelle explains the increasingly novel dynamics that surround fund behavior and what the world can come to expect from their growing presence in international financial markets. GJIA: When it comes to the roles sovereign wealth funds (SWFs) play in global markets and politics, what would you say makes them unique? Kathryn Lavelle: Sovereign wealth funds (SWFs) operate on behalf of governments as investors. That in itself is a strange relationship. Within them, a core contest takes place between the state’s interests (or sovereign) part of the dynamic, and the money interests (or wealth) part of it, and these two aspects are frequently in contradiction, serving fundamentally different goals. SWFs are also quite fascinating because when you talk to the people who manage these funds, they have an interest in convincing you that the decisions are made almost exclusively on a financial basis—they really will go to great lengths to differentiate their government owners and those who make the management decisions. At the same time, these people ultimately answer to someone in power. Therefore, for most SWFs, it remains deeply unclear who is actually making the investment decisions and for what purposes. Of course, it is not always clear how other vehicles, such as hedge funds and private equity make the decisions they do, but I think what a lot of people find particularly disconcerting about SWFs is that they seem to act on behalf of people who have a different identity from their own. People who could be trying to manipulate politics and markets in a way that would have a long-term effect on their own populations. Regular investors come and go at will, and they only share an interest in profit as far as most of us understand. However, SWFs have that extra “sovereign” part right behind them that obscures their true interest. GJIA: These funds can be found in countries all across the globe, in both authoritarian states and democracies. Would you say SWFs differ in their goals and structures between regime-type? KL: It is not necessarily regime type that makes the goals and structures of SWFs different. It has to do with their economies. Let’s look at a country like China. There’s going to be a debate about exactly how to characterize the regime, but it is a country with many different kinds of sovereign wealth funds, and a particularly opaque state connection to each. At one time, some of the state-owned Chinese oil companies created specialized investment vehicles listed outside Chinese markets that excluded parts of the firms that were more associated with human rights violations. At the same time, the China Investment Corporation (CIC)—China’s largest SWF—draws a lot of concern, not necessarily because of its investment activities, but because of the dynamics of global politics. So, I wouldn’t really tie differences to regime types themselves in a wholesale way, but rather to how such funds are perceived and how they are structured. Saudi Arabia’s SWF is getting all kinds of attention for its involvement in Hollywood, and this takes me right back to when I was a student in the 1980s, when people were concerned about Japanese investment entities buying assets in Hollywood. They aren’t quite the same in financial terms, but it’s the same kind of concern about foreign investment that drives people to be suspicious, and the whole idea that “foreigners are influencing Hollywood.” This holds true across industries, and it reflects where politics are in places like the United States right now. One metric we can try to look at is transparency, where all the funds will tell you, “we are transparent.” The problem you’ll keep running into with this approach is how you value things. When trying to do comparative studies of equity markets, you’ll find that every country doesn’t use Generally Accepted Accounting Principles like we do in the United States. A fund may appear opaque politically and not want people to show what they’re invested in or what their intent with that investment is, but they could also just not be able to report it because of the way it was purchased, or the kinds of shares they purchased. There are some assets out there that really are difficult to put a monetary value on. GJIA: To what extent do domestic politics shape SWF behavior in both the investing “home” country and the recipient “host” country? KL: This depends on the type of fund present and also on the extent to which voters’ political views are able to influence the fund. For example, in a democratic home state like Norway, the SWF doesn’t invest in nuclear weapons or tobacco because of social concerns, but there is a continuing debate over whether it should invest in oil, even though that’s where most of the money comes from. The degree to which Norway will continue to make those investments, and whether they contradict the government’s overall climate goals, is an open question in Norwegian politics. Because of the way the fund’s governance is structured, it may not be easy to resolve. On the other hand, some people consider pension funds, like the State Teachers Retirement System (STRS) in Ohio, to be quasi-SWF. They have a very strict separation between the people who make up the management division and the fund owners. No teacher or professor would want to invest in things that may harm the future of their students. At the same time, a fund manager might see an opportunity in a diversified multinational corporation that offers a good return, despite it deriving part of its revenue from e-cigarettes. These contests are very apparent. Domestic politics can work in host countries too. A good example is Singapore’s SWF, Temasek, investing in Thailand’s telecommunications sector. If you study political economy, you already know that countries everywhere are uncomfortable with foreign ownership of their telecom sectors because a foreign entity could monitor or manipulate our communications with each other. In the case of Temasek, there was significant pushback from Thai citizens surrounding the deal, which went on to influence national political sentiment toward Singapore as a whole, underscoring the risks some SWFs may face with their investment choices. In this case, fund behavior led to the dissolution of the entire Thai government in 2006 and a subsequent coup d’état. GJIA: To address some of this unease, the Santiago Principles were established in 2009 to ostensibly promote trust and transparency. From your perspective, have these mechanisms actually changed fund behavior? KL: In international relations theory, we always like to have a clear set of norms and best practices—the orientation we want the proverbial ship to be going in. In that regard, the Santiago Principles at least got the discussion going about which direction SWFs should take at a time when people were very skittish about the growing size of these funds. Nobody wanted them to be out there and potentially destabilizing economies, so talks about disclosure, conditions for withdrawal, and the independence of managers were helpful when initiated. The biggest stumbling block was that there wasn’t exactly a good way to measure compliance with the Principles, let alone how to hold funds to them. If you read the Principles, they’re overall quite vague. In general, a fund doesn’t want to reveal how and why they make certain investment decisions because that information is proprietary—a fund makes money off of how and why it makes decisions—so how do you reconcile that with loosely-defined ideas of openness? Some decisions might have a political purpose. The bottom line is that trying to figure out and assign a score to compliance is not easy, and it is therefore the reason why the Santiago Principles never really got off the ground to the point where they could truly direct fund behavior. GJIA: Many emerging markets are looking to build their own SWFs from mineral and oil revenues. Historically, have funds shaped development trajectories in these countries? KL: I think the big story in international emerging markets investment is that the investment is increasingly no longer unidirectional. In the past multinational corporations of primarily Western background were the main form of foreign direct investment in a country. That has changed dramatically, to the point where you have companies from so-called “developing countries” taking over companies in the United States. Therefore, the landscape of international investment has changed, and I think SWFs are certainly a possibility to be the next step in the game. Historically, you didn’t need an entire financial vehicle to reinvest commodity revenues in your country, but as emerging markets get more financially sophisticated, their capacity to operate such funds has increased. SWFs would allow treasuries to move from relying on holding foreign exchange assets like cash or government bonds to having broader financial markets and targeted growth areas, while easing pressure on welfare expenditures. GJIA: With their increasing financial weight, do you see the presence of SWFs being a factor in the political choices leaders will have to make with regard to domestic and foreign policy? KL: It will depend on just how big the funds get. One of the reasons people are already apprehensive is because of their scale, and if certain SWFs in certain countries achieve a large-enough size, the presence will absolutely be cause for concern. The other factor political leaders will have to consider are their objectives. It’s not always clear how to define a SWF, or even where its activity is concentrated, but it is certainly a worry from the perspective of national security of opaque external investment. More than that, I think one of the most interesting questions going forward is whether the United States, the home to the world’s largest financial markets, will develop its own fund, for which the Trump administration announced a plan. There have also been several proposals in Congress. Were it to come into being, it would have tremendous weight. At the same time, one of the hallmarks of U.S. capitalism is a lack of government ownership of shares, so it would not be clear how such a fund would be received in domestic politics, or which direction it would take. Given how politically fragmented the country is, a Democratic administration would likely be concerned about different sectors of the economy, such as healthcare, and want investment there, rather than a Republican administration, which might prefer defense industries. No investment vehicle could thrive under conditions of such instability. Moreover, it remains unclear where the money to fund a theoretical U.S. SWF would come from. It would be a fundamentally different entity depending on whether it is financed with debt, economic surplus, commodities, or the sale of state companies, as in the case of Singapore. If it is debt, or government borrowing of some form, then the fund would have to outperform whatever the cost of that debt is, which is not an easy thing to do. I think our political leaders have enough on their plate. Our system has worked well keeping political and investment functions generally separate. We have seen different forms of business rise and fall, and even the perception of different countries, all of which funds are tied to. Unless a major SWF either starts—like in the case of the United States—or collapses—an issue that concerns the Saudis, I don’t see any political tsunamis on the horizon. . . . Kathryn Lavelle is the Ellen and Dixon Long Professor of World Affairs at Case Western Reserve University in Cleveland, Ohio. Her research explores the exchange between domestic and international and political institutions with a particular emphasis on political economy and multilateralism. Dr. Lavelle’s first book, The Politics of Equity Finance in Emerging Markets, explored the political circumstances that surround large issues of stock in the developing world. After being granted tenure at Case Western, she was awarded an American Political Science Association Congressional Fellowship and named the William A. Steiger fellow, a designation given to the most promising political scientist in her class of fellows. While in Washington during 2006-2007, she worked on the staff of the House Committee on Financial Services on issues related to domestic and international monetary policy. Dr. Lavelle holds a PhD in political science from Northwestern University; an M.A. in government and foreign affairs from the University of Virginia; and a bachelor’s degree in international economics from Georgetown University. She is a permanent member of the New York Council on Foreign Relations. This transcript has been lightly edited for clarity and length. Interview conducted by Sid Mehrotra. Image Credit: Jason Leung, Unsplash Content Licenses, via Unsplash
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