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What a GOP loss in Trump’s Mar-a-Lago district says about the midterms
Including off-year elections last year, Democrats have flipped 30 Republican seats since the start of 2025.
Green Leader Polanski Says the UK Shouldn’t ‘Strangle’ Business
The leader of the UK’s insurgent Green Party said government shouldn’t be “strangling” business, as he tempered his left-wing bloc’s economic message ahead of nationwide local elections in May.
Green Leader Polanski Says the UK Shouldn’t ‘Strangle’ Business
The leader of the UK’s insurgent Green Party said government shouldn’t be “strangling” business, as he tempered his left-wing bloc’s economic message ahead of nationwide local elections in May.
Emily Gregory is Donald Trump's new state representative and a new hope for Democrats in Florida
Florida state Rep.-elect Emily Gregory is the latest face of Democrats' optimism after she won a special legislative election in President Donald Trump's home state House district. Florida Democrats...
States Brace for a Potential Supreme Court Ban on Late-Arriving Ballots
The court’s conservatives appear skeptical of laws allowing mail ballots to arrive after Election Day. A decision could come as late as June, potentially scrambling midterm elections.
Wednesday morning quarterback: If Republicans aren't scared after Special Election upsets, they should be
Guys and gals, this is not Chicken Little; the sky has already fallen.
Biden political priorities impeded Iran negotiations, former secretary of state admits
Former Secretary of State Antony Blinken admitted that midterm elections complicated the Biden administration's push for a stronger Iran nuclear deal.
Florida Democrat flips seat in special election in district that includes Trump’s Mar-a-Lago
Democrat Emily Gregory won a Florida special election on Tuesday, flipping a state legislative district that is home to Mar-a-Lago, the Palm Beach estate that President Donald Trump counts as his residence. The president had endorsed Gregory’s rival, Jon Maples. In a social media post Monday, he urged voters to turn out, saying Maples was backed “by so many of my Palm Beach County friends.” READ MORE: Trump casts Florida ballot by mail as he
Seahawks Survey: What will John Schneider do with pick 32?
Trade or stick and pick? What will the Seahawks do with their first-round selection?
Flavio Bolsonaro Inches Ahead of Lula in Brazil Election Poll
Flavio Bolsonaro edged ahead of President Luiz Inacio Lula da Silva in the run-up to October’s election, with a new poll showing for the first time that the right-wing senator is leading the race.
Trump votes by mail amid his push to end mail-in ballots
President Donald Trump cast a ballot by mail in the March 24 special election in Palm Beach, Florida, even though he has spent years attacking mail-in ballots as susceptible to fraud.
Democrat gets upset win in Trump’s backyard in Florida state house race
Emily Gregory won the special election to represent a district that includes President Donald Trump’s Mar-A-Lago home on Tuesday, the Associated Press projected.
Democrat flips seat in special election for Florida district that includes Trump’s Mar-a-Lago resort
Democrat Emily Gregory has won a special election for a Florida state House seat, flipping a district that is home to President Donald Trump’s estate, Mar-a-Lago
Democrat flips Republican-held Florida state House district that includes Trump’s Mar-a-Lago
Democrat Emily Gregory narrowly won the special election for the district on Tuesday night, The Associated Press projects. Trump carried the area in 2024.
Florida Democrats Win Special Election in Mar-a-Lago’s District
Emily Gregory’s victory brought the Democratic surge to President Trump’s backyard, Palm Beach, just weeks after her party won the mayor’s race in Boca Raton, 30 miles south.
Democrat Emily Gregory wins Special Election for HD 87 in Palm Beach County
Campaign messaging escalated in the final stretch, with disputes over residency and political tactics.
Ballot box upset: Democrats flip Florida legislative seat in Trump’s stomping ground
Trump-endorsed Republican Jon Maples loses to Democrat Emily Gregory in a Florida House District 87 special election in Palm Beach, home to President Donald Trump
Hilary Holley dominates HD 51 Special Election, will replace Josie Tomkow
Holley had both a fundraising advantage and more institutional support.
Joe Flacco returning to Bengals: 41-year-old QB set for 19th NFL season in 2026
Flacco is coming off his first Pro Bowl selection.
Joe Flacco reportedly agrees to return to Bengals
Flacco went 1-5 in his starts with the Bengals and earned a Pro Bowl selection.
Steve Kornacki's guide to the next big elections on the calendar: From the Politics Desk
Plus, where talks to end the DHS shutdown stand.
Danish Social Democrat Premier Takes Lead in Parliamentary Vote
Danish Prime Minister Mette Frederiksen’s party is on track to win the most seats in an election shaped by Donald Trump’s threats over Greenland, according to exit polls.
Missouri court upholds mid-decade congressional redistricting backed by Trump
A Missouri court has upheld a mid-decade redistricting plan that gives Republicans a chance to win an additional congressional seat in this year’s midterm elections
Billionaire OpenAI investor Vinod Khosla thinks 80% of jobs could vanish by 2030, and that ‘fear of AI’ put American politics in a chokehold
“The single biggest issue I believe in the 2028 presidential election will be fear of AI,” the Khosla Ventures founder said.
Age Comes for Us All—Even Politicians
Don’t look now, but the period from now through the 2028 presidential election will be a historic inflection point in our politics. We’ll see enormous generational change take place amid enormous uncertainty and volatility.
Ed Davey accuses Reform UK and Tories of importing ‘Trump-style divisive politics’
Lib Dems will focus on ‘rolling up their sleeves and getting things done’, leader says at launch of local election campaign
From elections to redistricting, Jenna Persons-Mulicka’s footprint grows in the House
For now, though, she’s enjoying a break from action back home with her sons.
In Oklahoma, Alan Armstrong Will Fill Markwayne Mullin’s Senate Seat
Gov. Kevin Stitt selected Mr. Armstrong, a fellow Republican and an energy executive, to play a caretaker role in the seat until the next election.
Crowded Democratic race for California governor could open door for Republicans
The candidates will clash on Tuesday at a debate.
ICE officers at airports a ‘test run’ for midterms, Steve Bannon suggests
Former White House strategist says current situation at airports will help ‘really perfect ICE’s involvement in the 2026 midterm elections’
Florida Democrats hope in special election to flip a state legislative district that includes Mar-a-Lago
Democrats in Florida are hoping to capitalize on the party’s recent special election overperformances and come out on top Tuesday in a special state House election for a Palm Beach district that includes President Donald Trump’s Mar-a-Lago residence.
Josh Shapiro endorses James Malone in key Lancaster County Senate race
Gov. Josh Shapiro has officially endorsed James Malone’s bid for reelection in the Lancaster County state Senate district that both parties say could determine party control next year.
The Supreme Court’s conservatives could significantly alter the 2026 election
The Supreme Court on Monday appeared ready to limit mail-in ballots, a move that would reinforce the justices’ pattern of shrinking voter protections and that has, at bottom, favored Republican interests and the Trump administration.
Dark money pours into Massachusetts politics
WBUR found a rise of dark money groups trying to sway local elections and influence policy. The nonprofits can raise and spend unlimited money from undisclosed donors. Watchdogs warn about their growing influence on Massachusetts politics.
‘It’s a big deal’: Election expert weighs in on the Supreme Court case that could upend midterms
Trump, Who Calls Mail-in Voting ‘Cheating,’ Just Voted by Mail
President Trump has long fixated on mail-in-voting to bolster his baseless claims of widespread voter fraud. But he recently used the method in a Florida special election.
We disagreed on politics. We agreed on wine. That was enough.
At the Virginia Governor’s Cup Gala in Richmond earlier this month, a very dapper gentleman approached me and introduced himself. In his light-colored suit and bowtie, he looked very Southern in a classical sense, the sort of Virginia Gentleman you used to see south of the Rappahannock as recently as my college days. “I’m a longtime reader and fan of your writing, if not your politics,” he said. His comment was the proverbial iron fist in a velvet glove, simultaneously conveying praise and disapproval while establishing boundaries. Man, I wish we still discoursed like this instead of shouting bromides and insults to try and “own” our opponents with a funny meme and a furrowed brow. Subscribe “Well, we’ll always have wine to share together,” I said, and thanked him for his kind words. We clinked glasses, exchanged pleasantries about the delicious gold medal-winning wines being poured that evening, and went our separate ways. Our exchange reminded me that more unites us than divides us. Wine brings people together to share a meal and a few hours of joy despite our differences.1 That’s why I refer to the wine community — including readers and consumers — rather than the wine industry. Together, we are so much more than production, distribution and sales statistics. A few minutes later the evening’s awards ceremony began. Applause grew as the 12 winemakers who made the top-scoring wines for the Governor’s Case took the stage, including a loud cheer for Jonathan Wheeler of Trump Winery and his 2018 Blanc de Noir sparkling wine. All the winemakers on stage had reason to be proud, Wheeler perhaps more so. Trump Winery was the only winery to win six gold medals in the competition this year. (Wineries are limited to six entries.) Two of Wheeler’s ciders also won gold medals in a separate competition. When you cover the labels and take the sour taste of politics off your palate, the wines are pretty darn good.2 Then Gov. Abigail Spanberger, newly elected Democrat and Virginia’s first female governor, was introduced to great applause to announce which of the 12 wines had won the Governor’s Cup. She spoke for a few minutes about the importance of wine to Virginia’s economy and tourism and the international acclaim Virginia wine has received. Just two weeks earlier, she gave the Democrats’ response to Trump’s State of the Union speech, but this night wasn’t about politics. That didn’t stop several people in the crowd from speculating on the irony should she have to present the trophy to Trump Winery. In the end, Valley Road Vineyards was displayed on the screen behind Spanberger as the winning winery. Blue Bee Cidery in Richmond took top honors for that category. The crowd cheered a female governor presenting the state’s highest trophy to a female winemaker and then resumed the evening’s festivities, united by their mutual love of wine. A whiff of politics couldn’t dim the cheer of celebration and a community united by its love of wine. In Memoriam: Michel Rolland The global wine community lost a giant March 20, with the passing of Michel Rolland. He was 78. Rolland was the original “flying winemaker,” a globe-trotting consultant who helped Bordeaux regain its mojo in the 1970s and then shaped the rise of Napa Valley cult Cabernet as consultant to Simi, Harlan, Newton, Screaming Eagle, Araujo, Dalle Valle and other wineries. He was instrumental in Argentina’s rise to prominence and even had his own winery, Clos de los Siete, in a partnership with other wine families. Rolland’s career arc paralleled that of Robert Parker, the world’s most influential critic. Parker championed many of the wines Rolland consulted on, helping build his reputation and demand for his services. It also made him a target for Parker’s critics. As W. Blake Gray wrote on Wine-Searcher in his excellent tribute to Rolland: Rolland created the type of wines Parker loved: rich body, plenty of fruit, soft tannins. He sometimes faced the accusation of creating a generic international style of red wine, where the great wines he made in Argentina were indistinguishable from the great wines he made in France. Rolland chafed at that critique, as did many of his fans. He was credited with championing green harvesting and leaf pulling, as well as careful selection of grapes in the winery, practices we nearly universally think of today for high-quality winemaking. “Michel was an incredible innovator who changed how wine was made and how grapes were grown,” Napa Valley winemaker Aaron Pott wrote on Facebook. “His work has transformed the wine trade. He created new ways of looking at wine, tasting wine, evaluating ripeness and quality. … This was not just a man with a ‘style’ that he imposed on vineyards but a man that understood how to make great wine from great sites.” Rolland started his consulting company in 1973 in Libourne, in Bordeaux, with his wife, Dany. Both had graduated the year before from Bordeaux’s Institute d’Oenologie. The couple sold their majority share in the business in 2020, according to Wine Spectator. Over his career, Rolland reportedly worked with more than 100 wineries in 20 countries. He even made it to Virginia, where he consulted for Kluge Estate in the mid-2000s. (Kluge Estate is now Trump Winery.) Reader feedback, please! Last week, I did my first WineLine Live! with Dr. Laura Catena of Catena Zapata winery in Argentina. We enjoyed a fascinating discussion about her efforts to preserve the genetic heritage of old vineyards in Mendoza. I conceived of WineLine Live! for paid subscribers, as a thank you for your financial support. And while only a few people joined live, the video now has more views than I have paid subscribers, so I guess that’s pretty good. Even so, I’m considering opening future installments to anyone on Substack to reach a broader audience. So my questions to you: Should these be public? And what format do you prefer? Live gives a chat feature with the potential for viewers to interact with me and the guest, while a video post would just be that. Another alternative is a podcast, which would just be audio, without video of my chins. Please let me know in the comments. Leave a comment In the Glass A few wines I’ve enjoyed recently: Bonny Doon Vineyard Take Me to Your Liter, Le Cigare Volant, Red Wine of the Earth. 2023, Central Coast, CA. Blend of Grenache, Syrah Cinsaut and Petite Sirah. Delightful wine with expressive red fruit flavors, casual drinking. Doon lovers of a certain age will remember Randall Grahm’s Big House Red; this is more in that style than his original Le Cigare Volant, modeled after Chateauneuf du Pape. The liter bottle makes it an even better value. I see this online at about $15. Great value. Albert Bichot Bourgogne Pinot Noir Origines 2023. 13% - Textbook pinot noir and an excellent, affordable entry (regional) Burgundy. Wine Enthusiast Top 100 Wines of 2025. $24 at Total Wine & More. Loma Larga Pinot Noir 2021 “Coastal Cool Climate Wine”, Valle de Casablanca, Chile. An older sample, showing beautifully. Spicy and fruit forward. I’m seeing widely varied pricing online, from $18-$32. At the lower end, it’s a terrific value. 13.5% Dr. Loosen Riesling Dry 2016, Mosel, Germany. Found this “in the stack.” And it stacked up well, shedding some of its youthful acidity for opulent Riesling character, including a hint of the mineral oil older Riesling often features. A great value, as I’m seeing it as low as $14 online. 12% abv. Red Tail Ridge Blau Franc Blend 2024, Sans Oak, Finger Lakes. 13.4% abv. The name is a neat portmanteau of Blaufrankisch and Cabernet Franc, thus Blau Franc. The blend is 50-50, no oak involved. The Blau dominates on the palate, with the spicy caraway seed (think New York deli rye bread). The Franc adds body. The result is juicy, energetic and joyful. Sokol Blosser Estate Rosé of Pinot Noir 2025, Dundee Hills, Willamette Valley, Oregon. This first rosé of 2025 was a welcome respite to our cold, snowy winter here in the Mid-Atlantic. Oh man, I needed this! Bright and energetic, exuberant even, it perks up the mood and goes down fast. 13%. Certified B Corp. Ingredient and nutrition labeling, and in a modest way that doesn’t occupy a lot of label space. (Since it’s not required, presumably there are no minimum font size requirements.) More wineries should follow this example. Dave McIntyre's WineLine is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Subscribe Thanks for reading Dave McIntyre's WineLine! This post is public so feel free to share it. Share 1 Some restraint may be required. 2 Especially the bubblies.
Trump casts mail ballot in Florida even as he calls the method 'cheating'
The president cast a mail ballot in an upcoming Florida special election, according to county records.
Dems hope for long-shot upset in SD 14 Special Election between Josie Tomkow, Brian Nathan
Early voting, voter registration and fundraising data suggests Nathan will come up short, but there could be a silver lining for Democrats.
Special election on Tuesday will test whether national political winds reach Florida
Tuesday is a special election day for 300,000 voters in Florida's Senate District 14.
Former political rivals take on Trump’s push to nationalize voting
GOP lawyer Ben Ginsberg and former Obama White House counsel Bob Bauer aim to present a united front against the Trump administration’s efforts to oversee election administration
It’s a Chaotic Moment in America. That’s Not What Republicans Need.
A national mood of unease and anxiety ahead of major elections is rarely good for the party in power.
Democratic and Republican Party officials face internal backlash after primaries
Party officials have received calls to resign amid endorsements and campaign spending in national and state primary elections.
Takeaways from arguments in the Supreme Court case that could end grace periods for mail-in ballots
The Supreme Court’s conservative majority appeared dubious of state laws that allow the counting of mail ballots that arrive at election offices after Election Day as justices heard oral arguments in a challenge to Mississippi’s five-day grace period for mail ballots.
Supreme Court leans toward Trump-backed push to limit mail-in ballots
The Supreme Court's conservative majority seemed skeptical of late- arriving ballots. The case could lead to stricter rules in this year's midterm elections.
Californians may need to mail ballots early as Supreme Court signals support for new election day deadline
California counts mail-in ballots that arrive up to seven days after election day, but that option may be deemed illegal
On eve of SD 14 election, Dems still lag in early vote, but data suggests possible victory in defeat
Even if Democrat Brian Nathan loses, an overperformance could send a big message.
Exit polls suggest Italy's Meloni has narrowly lost justice referendum vote
Exit polls on Monday suggested Italian Prime Minister Giorgia Meloni had narrowly lost a referendum on her flagship reform of the judicial system, dealing a potential blow to the ruling coalition ahead of next year's general election.
Supreme Court hears arguments in mail-in voting case
The Supreme Court is hearing arguments today in a case about whether states may count mail-in ballots received after Election Day. Follow here for live updates.
Republicans fear this Democrat in Georgia Senate race: ‘This guy’s no slouch’
The Cook Political Report rates the general election as a toss-up.
Emmanuel Grégoire, Socialist long involved in local politics, voted new Paris mayor; AP explains
Grégoire won over 50% of the votes, beating out prominent conservative contender Rachida Dati who reached 41% while hard-left contender Sophia Chikirou got about 8%.
Mailer in Germantown school election has one big problem
An outside political group urges Germantown School District voters to re-elect a candidate who isn't on the ballot.
Ohio lawmaker proposes election board changes after Delaware County dispute
Dispute at the Delaware County Board of Elections prompted a state lawmaker to propose changes to how county election boards work.
In California, a Republican Sheriff Seizes Ballots, Prompting Concerns
Riverside County Sheriff Chad Bianco, a candidate for governor, recently took possession of more than 650,000 ballots as part of a fraud probe. Election officials say his investigation is baseless.
As mayoral election looms, D.C.’s business class worries about what’s next
A potential leftward shift in the wake of the pandemic and the Trump administration’s cutting of thousands of federal jobs has sparked unease in the city’s business community.
‘Anyone but Labour’ or ‘anyone but Reform’? Clash of animosities likely to define May local elections
While Labour braces for a rout that could see off Starmer, a rising drive to keep out Farage is complicating expectations
What’s at stake for UK in May’s local elections: six key questions
Reform, Plaid Cymru, the SNP and the Greens are all banking on big gains and nationwide repercussions
Breaking the Cycle review – meet the charismatic Thai politician striving to change his country’s history
Gripping documentary examines the Future Forward Party’s unprecedented 2019 election result, and its leader’s aim to break Thailand’s repeated military coups
French Local Elections Are Yardstick for Far Right. Initial Results Are Mixed.
France’s municipal elections ended on Sunday evening. Full results were not expected for hours, but the first projections suggested the far right may not have made major gains.
Slovenia liberals take narrow election lead over conservatives: exit poll
Exits polls suggest Prime Minister Robert Golob has blocked a fourth term for right-winger Janez Janša
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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