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Saturn's moon Titan could harbor life, but only a tiny amount, study finds

Source: {'href': 'https://www.sciencedaily.com', 'title': 'ScienceDaily'} Published: 2025-04-07 23:31:59

Titan, Saturn's largest moon, is a strange, alien world. Covered in rivers and lakes of liquid methane, icy boulders and dunes of soot-like "sand," its topography has long fascinated scientists and invited speculation on whether lifeforms might lurk beneath the moon's thick, hazy atmosphere. An international team of researchers co-led by Antonin Affholder at the U of A Department of Ecology and Evolutionary Biology and Peter Higgins at Harvard University's Department of Earth and Planetary sciences set out to develop a realistic scenario of what life on Titan might look like if it does exist, where it is most likely to occur and how much of it might be present. "In our study, we focus on what makes Titan unique when compared to other icy moons: its plentiful organic content," said Affholder, who is a postdoctoral research associate. Using bioenergetic modeling, the team found that Titan's subsurface ocean, estimated to be as deep as about 300 miles, may support lifeforms that consume organic material. Published in The Planetary Science Journal, their study concludes that while Titan could possibly harbor simple, microscopic life, it likely could support only a few pounds of biomass overall. Often described as "Earthlike on the surface, ocean world on the inside," Titan is the target for future exploration via NASA's Dragonfly mission. While much has been speculated about possible scenarios that could give rise to living organisms on Titan based on the moon's abundant organic chemistry, previous estimates have suffered from what Affholder considers an overly simplistic approach. "There has been this sense that because Titan has such abundant organics, there is no shortage of food sources that could sustain life," Affholder said. "We point out that not all of these organic molecules may constitute food sources, the ocean is really big, and there's limited exchange between the ocean and the surface, where all those organics are, so we argue for a more nuanced approach." At the core of the research lies a "back-to-basics" approach that attempted to come up with a plausible scenario for life on Titan that assumed one of the simplest and most remarkable of all biological metabolic processes: fermentation. Familiar to Earthlings for its use in sourdough breadmaking, beer brewing and -- less desirably -- its role in spoiling forgotten leftovers, fermentation only requires organic molecules, but no "oxidant" such as oxygen, a crucial requirement for other metabolic processes, such as respiration. "Fermentation probably evolved early in the history of Earth's life, and does not require us to open any door into unknown or speculative mechanisms that may or may not have happened on Titan," Affholder said, adding that life on Earth could have first emerged as feeding on organic molecules left over from Earth's formation. "We asked, could similar microbes exist on Titan?" Affholder said. "If so, what potential does Titan's subsurface ocean have for a biosphere feeding off of the seemingly vast inventory of abiotic organic molecules synthesized in Titan's atmosphere, accumulating at its surface and present in the core?" The researchers specifically focused on one organic molecule, glycine, the simplest of all known amino acids. "We know that glycine was relatively abundant in any sort of primordial matter in the solar system," Affholder said. "When you look at asteroids, comets, the clouds of particles and gas from which stars and planets like our solar system form, we find glycine or its precursors in pretty much all those places." However, computer simulations revealed that only a small fraction of Titan's organic material may be suitable for microbial consumption. Glycine-consuming microbes in Titan's ocean would depend on a steady supply of the amino acid from the surface, through the thick icy shell. Previous work by the same team had shown that meteorites impacting the ice could leave behind "melt pools" of liquid water, which then sink through the ice and deliver surface materials to the ocean. "Our new study shows that this supply may only be sufficient to sustain a very small population of microbes weighing a total of only a few kilograms at most -- equivalent to the mass of a small dog," Affholder said. "Such a tiny biosphere would average less than one cell per liter of water over Titan's entire vast ocean." For a future mission to Titan, the odds of finding life -- if it is indeed there -- could be like looking for a needle in a haystack, unless Titan's potential for life is to be found elsewhere than in its surface organic content, the team suggests. "We conclude that Titan's uniquely rich organic inventory may not in fact be available to play the role in the moon's habitability to the extent one might intuitively think," Affholder said. The International Space Science Institute, or ISSI in Bern, Switzerland, funded the research. Story Source: Materials provided by University of Arizona. Original written by Daniel Stolte. Note: Content may be edited for style and length. Related Multimedia: Journal Reference: Cite This Page: Stay informed with ScienceDaily's free email newsletter, updated daily and weekly. 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Diagnostic uncertainty in Parkinson's disease: Study calls for improved diagnostic processes

Source: {'href': 'https://www.sciencedaily.com', 'title': 'ScienceDaily'} Published: 2025-04-07 23:29:52

A new study by the University of Turku and Turku University Hospital, Finland, found that a significant proportion of Parkinson's disease diagnoses are later corrected. Up to one in six diagnoses changed after ten years of follow-up, and the majority of new diagnoses were made within two years of the original diagnosis. A recent study published in Neurology reveals significant diagnostic instability in Parkinson's disease, with 13.3% of diagnoses revised over a 10-year follow-up period. When dementia with Lewy bodies (DLB) is treated as a separate diagnostic category, the revision rate increases to 17.7%. The large-scale study followed over 1,600 patients initially diagnosed with Parkinson's disease. The results demonstrate the ongoing difficulty of distinguishing it from other similar disorders, despite improvements in diagnostics. "Notably, a majority of these diagnostic changes occur within the first two years of diagnosis, which emphasises the challenges and uncertainty clinicians face in diagnosing Parkinson's disease accurately," explains Valtteri Kaasinen, Professor of Neurology at the University of Turku and principal investigator of the study. Clinical practices and diagnostic challenges increase misdiagnoses Commonly revised diagnoses included vascular parkinsonism, progressive supranuclear palsy, multiple system atrophy, and clinically undetermined parkinsonism. While dopamine transporter (DAT) imaging was frequently used to aid in diagnosis, the study found that postmortem neuropathological examinations were only conducted in 3% of deceased patients, with 64% of these confirming the initial Parkinson's disease diagnoses. This decline in postmortem examinations mirrors a global trend seen in other studies. The study also highlights the difficulty in differentiating between Parkinson's disease and dementia with Lewy bodies, particularly in relation to the controversial "one-year rule." "This rule, which considers the temporal sequence of motor and cognitive symptoms, resulted in more latter cases identified compared to the original clinical diagnoses. While the one-year rule is used in clinical practice, its relevance may be limited by the overlap between these disorders, with substantial group-level differences but minimal distinctions at the individual level," says Kaasinen. Urgent need for improved diagnostic processes "The key conclusions of our study are the urgent need for ongoing refinement of diagnostic processes, enhanced clinical training for neurologists, more frequent use of postmortem diagnostic confirmation, and the development of widely accessible, cost-effective biomarkers," Kaasinen summarises. Increasing the rate of autopsies would enhance clinicians' understanding of diagnostic accuracy, particularly in cases where initial diagnoses are unclear or revised. The development of cost-effective and accessible biomarkers could improve diagnostic precision, particularly in non-specialised settings, ultimately leading to better patient care. This retrospective study was conducted at Turku University Hospital and three regional hospitals in Finland, analysing patient records from 2006 to 2020. The study aimed to evaluate the long-term diagnostic stability of Parkinson's disease and assess the accuracy of initial diagnoses over time in a large cohort of patients diagnosed by neurologists, with or without specialisation in movement disorders. Story Source: Materials provided by University of Turku. Note: Content may be edited for style and length. Journal Reference: Cite This Page: Stay informed with ScienceDaily's free email newsletter, updated daily and weekly. Or view our many newsfeeds in your RSS reader: Keep up to date with the latest news from ScienceDaily via social networks: Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?

Consciousness Formed Before Life Itself, Scientists Say—And the Evidence Could Be in This Asteroid Sample

Source: {'href': 'https://www.popularmechanics.com', 'title': 'Popular Mechanics'} Published: 2025-04-07 20:49:00

Tantalizing clues in the 4-billion-year-old asteroid Bennu samples could indicate the molecular formations that some scientists say support the workings of consciousness. Every six years, an asteroid by the name of Bennu passes by Earth. Bennu is a small, loosely compacted ball of black rocks that formed nearly 4.6 billion years ago. Recently, scientists accomplished an unprecedented feat, sending a spacecraft billions of miles to the asteroid and back to collect 121.6 grams of material from Bennu for study at an Arizona State University lab. NASA tasked the OSIRIS-REx team that retrieved material from Bennu to examine it for clues to the nature and origins of life. Tantalizing evidence in the Bennu sample suggests that the asteroid contains constituents of the “primordial soup” that scientists believe likely led to life emerging on Earth. But that's not all. It could also contain particular molecules that could have formed crystalline formations that some scientists believe are key to consciousness. These formations may have been present among organic molecules for a hundred million years before genes existed, enabling the earliest forms of decision-making and self-organization into life. According to Dr. Stuart Hameroff, a former anesthesiologist and one of the world's leading experts on consciousness, the director of the Bennu team, Dante Lauretta, reached out to him before they had received the samples. Both are at Arizona State University. Lauretta was wondering how one might find signs of life in the material they were about to receive and found an intriguing paper by Dr. Hameroff on the nature of consciousness and carbon molecules. The prevailing theory of consciousness is that humans manufacture it inside the brain—that it boils down to a computation. Yet, Dr. Hameroff and his collaborator, Nobel Laureate and physicist Roger Penrose, have argued for decades that consciousness made the world and not the other way around. They believe that it is not manufactured in the brain but only processed there, via an external quantum wave function sweeping through the universe that interacts with tiny protein tubes. These microtubules form the cytoskeleton of living cells and are especially plentiful in brain cells. Hameroff, Penrose and their collaborator, physicist and oncologist Jack Tuszyński demonstrated in 2023 that quantum activity in the brain could take place in these microtubules. According to this idea, known as Orchestrated Objective Reduction theory, conscious moments occur almost constantly as the quantum wave function collapses, creating moments of conscious awareness. Hameroff names this quantum wave function proto-consciousness or “dream state” consciousness. Their other collaborator, quantum mechanics expert Anirban Bandyopadhyay, Ph.D., calls it the music of the universe. Consciousness in the universe can be compared to a Tibetan singing bowl. When you run a mallet around the rim of the bowl, the sound grows as the vibration from the mallet resonates in the bowl. The longer you run the mallet around the bowl, the louder the song gets as the vibrational resonance increases. When universal consciousness, or the music of the universe, hits the consciousness chambers of the microtubules, the resonance grows like the mallet and the bowl. And here's where Bennu comes in. The asteroid is made up of carbons—the molecules that form the basis of all life. Researchers found that the samples include 14 of the 20 amino acids that life on Earth uses to make proteins. The bits of rock also contain all five nucleobases used to store and transmit genetic instructions in more complex biomolecules, such as DNA and RNA. Plus, the team found salts, evidence that the larger space object which Bennu broke away from may have contained a similar primordial soup to Earth's own, 4 billion years ago. These are all signs pointing to Bennu as a repository of life's precursors. But what about signs of consciousness? Bennu also could contain the structures that allow the kind of quantum resonance Hameroff believes are needed for consciousness. These are organic ring molecules whose extra electrons form electron clouds that exchange photons, as in fluorescence. Organic rings are key components of biomolecules, and if you have a bunch forming a specific, periodic crystalline formation—like an array or lattice—Hameroff says they become quantum oscillators that are able to support consciousness. In the human brain, he said, it's these quantum oscillators in our microtubules that give us our conscious experiences. Neurons are incredibly complex. Each neuronal cell comprises billions of microtubules that are oscillating, or passing electrons back and forth, at the astonishing speed of 1015 times per second. Conventional brain studies have only looked at brain activity in a narrow range—frequencies around 40 hertz, or cycles per second, in the millisecond time range. But Anirban Bandyopadhyay and his team at Japan's National Institute of Material Sciences found that there are, in fact, three bands of frequencies that conduct electricity at the neuron level; three bands of higher frequencies at the microtubule level; and three bands of even higher frequencies at the level of tubulin—the material microtubules are made of. Within each frequency another three bands of frequencies operate: a triplet of triplets. Bandyopadhyay's team concluded that most cognitive, perceptive, and emotional bursts occur around 200–700 nanoseconds. They believe this triplet of triplets pattern of resonance is a fundamental pattern of the universe. It's also found in DNA, RNA and other molecules, Hameroff said, so they hope to find evidence of it in the Bennu material. The asteroid material, of course, is not as complex as a neuron. However, Hameroff postulates that while the earliest qualia—conscious experiences—would have been random, organisms experiencing the pleasure of a spark of consciousness would have sought more. They would have experimented and organized themselves in such a way as to maximize the likelihood of creating another such experience. After all, even single celled organisms eat, swim around, have sex. Hameroff thinks these polyaromatic ring molecules might have organized themselves to increase opportunities for conscious quantum experiences. Lauretta says that polyaromatic ring molecules are everywhere in space, including in interstellar dust. “These are the same molecules which are the basis of organic chemistry, and life,” Hameroff says. “So we realized cooperative quantum oscillations among polyaromatics might be signs of life we could test in Bennu samples.” Meanwhile, Hameroff is working to demonstrate that anesthesia works to block consciousness by blocking electrical signals between molecules in the microtubules. That might be all it takes to interrupt consciousness. If found, Lauretta says a test using anesthesia gases might block the oscillations, just as in human brains. “We could claim some justification for consciousness being present and causal at life's origins.” Susan Lahey is a journalist and writer whose work has been published in numerous places in the U.S. and Europe. She's covered ocean wave energy and digital transformation; sustainable building and disaster recovery; healthcare in Burkina Faso and antibody design in Austin; the soul of AI and the inspiration of a Tewa sculptor working from a hogan near the foot of Taos Mountain. She lives in Porto, Portugal with a view of the sea. Humanity Is Closer Than Ever to Living Underwater This Strange Stuff May Be Older Than the Cosmos China's New Barges Are Unlike Any Other Ship Scientists May Have Killed Alien Life 50 Years Ago AI Study Says Shakespeare Didn't Write Some Plays How Tech Bros Almost Killed America's New Fighter Is America's Hypersonic Missile Finally Ready? Could Salt Help Power Floating Nuclear Reactors? How to Paint a Car ‘Dinosaur' Sightings Are on the Rise in the Congo This Battery Has Practically Unlimited Energy Conscious ‘Alien Minds' Could Be Living Among Us A Part of Hearst Digital Media We may earn commission from links on this page, but we only recommend products we back. ©2025 Hearst Magazine Media, Inc. All Rights Reserved.

Multifaceted nature of defect tolerance in halide perovskites and emerging semiconductors

Source: {'href': 'https://www.nature.com', 'title': 'Nature'} Published: 2025-04-07 19:13:22

HER2 testing: evolution and update for a companion diagnostic assay

Source: {'href': 'https://www.nature.com', 'title': 'Nature'} Published: 2025-04-07 17:28:04

Long COVID activists fought Trump team's research cuts and won ― for now

Source: {'href': 'https://www.nature.com', 'title': 'Nature'} Published: 2025-04-07 17:26:25

Weather Forecast Could Become Less Accurate with Trump Administration Deciding to Halt Upkeep of Critical Satellites

Source: {'href': 'https://www.scientificamerican.com', 'title': 'Scientific American'} Published: 2025-04-07 15:30:00

April 7, 2025 5 min read NOAA Halts Upkeep of Critical Weather Satellites The decision by the Trump administration to defer maintenance of the Joint Polar Satellite System threatens to degrade the accuracy of weather forecasts By Scott Waldman & E&E News Unlike geostationary satellites, polar-orbiting satellites capture swaths of data throughout the full globe, and observe the entire planet twice each day. This global mosaic, captured by the VIIRS instrument on the NOAA-21 satellite, is a composite image created from these swaths over a period of 24 hours between Dec. 5 and Dec. 6, 2022. NOAA STAR VIIRS SDR team CLIMATEWIRE | NOAA has begun to limit the work it devotes to maintaining a pair of polar weather satellites — putting at risk the accuracy of both weather forecasts and extreme storm predictions, say former agency officials. The move, outlined in a memo obtained exclusively by POLITICO's E&E News, calls on the agency to take a “minimum mission operations approach” to the two probes. The satellites are part of the Joint Polar Satellite System, which serves as the backbone of three- and seven-day forecasts and early warnings for hurricanes and tornadoes. The order means NOAA won't do much to upkeep the satellites, which orbit the Earth's poles 14 times a day. The March 28 memo calls for the deferral of discretionary activities including “modernization product maturation, flight software updates, decommissioning planning, ground system sustainment deployment(s), special calibrations, etc.” If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today. The reason for the move is because of anticipated “reduced flight engineering support,” according to the memo. The decision to defer the satellites' maintenance comes as the Trump administration slashes NOAA's contracts with outside vendors and looks to cut its workforce in half. Former NOAA officials warn the move is a short-sighted decision with potential long-term consequences. Deferring software updates and other maintenance work may save some money right now, but the approach increases the risk of failure and could drive up costs in the long-term, said Rick Spinrad, who served as NOAA administrator in the Biden administration. “As soon as you start having system glitches — and in the satellite world, system glitches are the name of the game — they're going to fail to collect the data they need,” Spinrad said. The stakes for failure are high. JPSS “provides the majority of data that informs numerical weather forecasting in the U.S. and delivers critical observations during severe weather events like hurricanes and blizzards,” according to NOAA. This image by the NOAA-21 satellite shows global water vapor. Image processing by NOAA/Center for Satellite Applications and Research. Contributors: Mark Liu, Ninghai Sun, NOAA/NESDIS/STAR; Vince Leslie, MIT-LL, JPSS ATMS SDR Team In a worst-case scenario, a failure could blind the country to a severe storm, potentially for days if the system has a significant issue, Spinrad said. It's unclear how much money the move will save. The section of the NOAA memo related to cost savings was left blank, and NOAA officials did not respond to a request for comment. The total cost of the JPSS program was estimated at more than $13 billion, according to NOAA. As it stands, the JPSS program is only partially complete. The oldest polar-orbiting satellite in the JPSS constellation is the Suomi National Polar-orbiting Partnership, which monitors long-term climate trends and biodiversity. That satellite was launched in 2011 and is nearing the end of its lifespan. Two additional JPSS satellites are set to join the three in space right now, with the next one scheduled to launch no earlier than 2027. The federal government, during the Biden administration, signed a roughly $100 million contract for that launch with SpaceX, the rocket company run by billionaire Elon Musk, an ally of President Donald Trump. Since Trump took office, Musk has led an aggressive campaign to slash both government spending and the size of the federal workforce, including at NOAA. A fifth satellite is also in development and scheduled to launch in 2032. No one in the Trump administration has yet raised the possibility of canceling one or both future launches. The new plan means NOAA and NASA will be less prepared to handle major issues that arise in the functioning of the satellites, according to Spinrad. Regular maintenance allows for problems to be addressed before they become serious. If something more serious were to occur, and the other satellites were also experiencing issues, the essential stream of weather monitoring data could be compromised for days, according to Spinrad. Artist's rendering of NOAA's JPSS-2. NOAA/Wikipedia Spinrad likened it to driving around in a car that could be disabled at any point while placing confidence on a second backup car parked in a garage with a dead battery or oil leak that no one has checked in years. The likelihood of a series of cascading failures notably increases without regular maintenance, he said. Data from the satellites — which are about as big as a pickup truck and powered by solar arrays — is shared with other governments, who pass along their data to the United States, Spinrad said. It's part of a collaborative global system of weather monitoring. For example, if a U.S. satellite collects data at one time of day, a European satellite might collect it later in the day. Collectively, they offer a comprehensive overview of global conditions that offer insights on incoming weather. Losing a data stream — through the loss of a satellite, for instance — can erode the overall accuracy of this collaboration. That's a real risk, Spinrad said, because satellites need constant maintenance. Their orbits need to be monitored and occasionally repositioned, the sensors need to be checked to ensure they are working properly and data transmission has to be evaluated as well. That long checklist is part of the reason former NOAA officials are arguing against the anti-upkeep order. The cuts to the maintenance of the satellites is similar to last week's proposed termination of a cloud usage contract for dozens of NOAA websites centered on climate change, extreme weather research and drought monitoring information. That termination would have destroyed a significant amount of research that would have been unrecoverable if the web pages were knocked offline. After news of the contract cuts became public, NOAA political appointees backed off the plan. Andrew Rosenberg, who served as a senior official at NOAA during the Clinton administration, said the latest memo shows the NOAA cuts are being driven by officials who don't understand the cost and consequence of what they are eliminating. “Are you really saying that maintenance of high tech, extremely expensive equipment that provides vital information is waste, fraud or abuse?” he asked. The move to defer the NOAA satellites' upkeep is happening as three NASA satellites that provide essential climate and atmospheric data near the end of their life. These probes could be offline within the year, and there are no plans to replace some of their specialized instruments, which provide information on long-term changes to the Earth's ozone layer, planet-warming solar radiation and other key climate information. One instrument for which there is no replacement plan is the Moderate Resolution Imaging Spectroradiometer, which tracks forests, clouds, glaciers and oceans. Scientists are hoping the NOAA satellites make up for that loss. Reprinted from E&E News with permission from POLITICO, LLC. Copyright 2025. E&E News provides essential news for energy and environment professionals. Scott Waldman is a reporter for E&E News. E&E News provides essential energy and environment news for professionals. Learn and share the most exciting discoveries, innovations and ideas shaping our world today. Follow Us: Scientific American is part of Springer Nature, which owns or has commercial relations with thousands of scientific publications (many of them can be found at www.springernature.com/us). Scientific American maintains a strict policy of editorial independence in reporting developments in science to our readers. © 2024 SCIENTIFIC AMERICAN, A DIVISION OF SPRINGER NATURE AMERICA, INC.ALL RIGHTS RESERVED.

Weak asthenosphere beneath the Eurasian interior inferred from Aral Sea desiccation

Source: {'href': 'https://www.nature.com', 'title': 'Nature'} Published: 2025-04-07 15:18:13

Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans

Source: {'href': 'https://www.nature.com', 'title': 'Nature'} Published: 2025-04-07 15:03:09

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Advertisement Nature Metabolism (2025)Cite this article Metrics details Environmental thermal stress substantially affects cellular plasticity of thermogenic adipocytes and energy balance through transcriptional and epigenetic mechanisms in rodents. However, roles of cold-adaptive epigenetic regulation of brown adipose tissue (BAT) in systemic energy metabolism in humans remained poorly understood. Here we report that individuals whose mothers conceived during cold seasons exhibit higher BAT activity, adaptive thermogenesis, increased daily total energy expenditure and lower body mass index and visceral fat accumulation. Structural equation modelling indicated that conception during the cold season protects against age-associated increase in body mass index through BAT activation in offspring. Meteorological analysis revealed that lower outdoor temperatures and greater fluctuations in daily temperatures during the fertilization period are key determinants of BAT activity. These findings suggest that BAT metabolic fate and susceptibility of metabolic diseases are preprogrammed by the epigenetic inheritance of cold exposure before the fertilization in humans. Obesity is the major risk factor for the development of type 2 diabetes, dyslipidaemia and cardiovascular diseases, increasing all-cause mortality1,2. While exercise habits and eating behaviours are important for energy homeostasis, environmental stimuli also influence the risk of obesity due to dynamic fluctuations in energy expenditure (EE)3. Cold exposure is a well-established environmental determinant of whole-body EE, triggering adaptive thermogenesis through the activation of metabolic organs, including brown adipose tissue (BAT)3,4. Individual differences in BAT activity are associated with age-related increases in body mass index (BMI), visceral fat accumulation, insulin resistance and cardiometabolic risks5,6,7,8. Despite the potential of BAT as a therapeutic target, underlying factors contributing to individual differences in BAT activity remain poorly understood, particularly in humans. Environmental regulation of adipose tissue thermogenesis differs between acute and chronic activation. In small rodents, acute cold exposure (for a few minutes) evokes immediate heat production in BAT through activation of the sympathetic nervous system and β-adrenergic signalling pathways9. Conversely, prolonged cold exposure (several weeks) induces de novo brown adipocyte differentiation and the appearance of beige adipocytes, which require chromatin conformation changes and histone modifications orchestrated by epigenetic regulators such as JMJD1A, limiting metabolic disorders10,11. Consistently, in humans, acute cold exposure for a few hours elicits BAT thermogenesis and substrate utilization, which correlate with sympathetic innervation12,13,14,15,16. Moreover, repeated cold exposure or chronic administration of an adrenergic receptor agonist for several weeks increases BAT activity and mass, ultimately improving adiposity and insulin sensitivity12,17,18. Transcriptomic analyses revealed that BAT in the supraclavicular depots of human adults resembles mouse beige adipocytes; in addition, expression of the epigenetic regulator JMJD1A in adipose tissue negatively correlates with BMI19,20,21. These consistent findings across species suggest that epigenetic mechanisms contribute to the recruitment of BAT in humans as it does in mice22,23. Genetic inheritance of risk alleles in thermogenic genes can also influence BAT activity as evidenced by the accelerated age-related decline in BAT and visceral fat accumulation in human adults with single nucleotide polymorphisms on uncoupling protein 1 (UCP1) and β3 adrenergic receptor (ADRB3)24. Compelling evidence also suggests that epigenetic predisposition induced by specific nutritional and environmental stresses such as temperature during gestation and lactation can be inherited across generations, resulting in various physiological alterations in experimental animals25,26,27,28. Building on these findings, we hypothesized that meteorological exposures experienced by parents before and during gestation influence BAT metabolic fate and regulate energy homeostasis in human offspring. This hypothesis is supported by a recent study in mice, demonstrating that preconception cold exposure, particularly within the paternal lineage, enhances adipose tissue thermogenesis in offspring through mechanisms possibly involving DNA methylation in sperm28. We present evidence that BAT metabolic activity, as well as adaptive EE, are elevated in healthy human individuals conceived during a cold season compared with those conceived during a warm season. Moreover, we performed a spatiotemporal meteorological analysis and identified a lower ambient temperature and larger diurnal temperature variation in the period before conception as critical determinants of BAT activity. Additionally, BAT activation resulting from preconception cold exposure was associated with a reduced BMI and waist circumference independent of age, sex and the season of birth. These findings provide comprehensive evidence suggesting that thermal stress experienced just before conception plays an intergenerational role in facilitating the activation and sustenance of BAT and modulating systemic energy homeostasis in humans. To investigate the lifelong effects of early-life environmental exposure on BAT function, we examined the association of cold-induced BAT activity with the seasons of fertilization or birth in 356 healthy young male volunteers (Cohort 1; Fig. 1a, Extended Data Fig. 1a and Supplementary Fig. 1a). The presence of detectable BAT and its quantitative metabolic activity were assessed with fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT) following cold exposure at 19 °C for 2 h (Fig. 1b)5,8,12,14. Based on the participant's day of birth, the seasons of birth and fertilization were categorized as either warm season (16 April through 16 October) or cold season (the remainder) (Extended Data Fig. 1b,c). Note that the seasonality of meteorological factors is distinct and rather coherent regardless of the latitude in the main islands of Japan, and the participant's place of birth distributed throughout Japan (Extended Data Fig. 1b,d). The prevalence of detectable BAT (high BAT) was indistinguishable between participants born in the cold season (cold birth group, 71.8%) and those born in the warm season (warm birth group, 73.8%, P = 0.381; Fig. 1c and Extended Data Fig. 2a). In contrast, BAT prevalence was significantly higher in those conceived in the cold season (cold fertilization group, 78.2%) than in those conceived in the warm season (warm fertilization group, 66.0%, P = 0.007; Fig. 1d and Extended Data Fig. 2b). Similarly, quantitative BAT activity was notably higher in the cold fertilization group than in the warm fertilization group (P = 0.017; Fig. 1e), whereas BAT activity was not associated with the season of birth (P = 0.144). The association between the fertilization season and BAT activity (adjusted odds ratio (OR) = 1.949, P = 0.007) was irrespective of age, BMI and the season of birth (Extended Data Fig. 2c). The effect of fertilization season is not specific to the supraclavicular BAT because fertilization in cold period was associated with increased number of active BAT depots, including thoracic, cervical, axillary, mediastinal and perirenal regions (Extended Data Fig. 2d–g). These suggest an intergenerational activation of BAT by preconception perceived environmental stress in young healthy men. These findings are not dependent on our method to define the seasons because the difference between our unbiased definition and another definition based on the median of outdoor temperature was only 2.7% of the year (10 days), having a negligible impact on the results. a, Study protocol for investigating intergenerational control of BAT in humans. BAT activity and density were assessed by 18F-FDG-PET/CT following acute cold exposure and NIR-TRS, respectively. The day of fertilization was estimated based on the day of birth. Seasons of birth and fertilization were determined according to the participant's days of birth and fertilization as depicted in Extended Data Fig. 1b. b, Cold-induced BAT activity assessed as FDG uptake value (standardized uptake value; SUV) of the high and low BAT groups in Cohort 1. High BAT group (n = 259), low BAT group (n = 97). c, Association of the prevalence of cold-activated BAT and the season of birth in b. Warm birth group (n = 188), cold birth group (n = 168). d, Association of prevalence of cold-activated BAT and the season of fertilization in b. Warm fertilization group (n = 159), cold fertilization group (n = 197). e, Cold-induced BAT activity assessed as FDG uptake value (SUV) in c and d. f, BAT density (BAT-d) of the high and low BAT-d groups assessed as total haemoglobin concentration, [total Hb], in the supraclavicular region in Cohort 2. High BAT-d group (n = 143), low BAT-d group (n = 143). g, Association of the percentage of participants with high BAT-d and season of birth in f. Warm group (n = 144), cold birth group (n = 142). h, Association of the percentage of participants with high BAT-d and season of fertilization in f. Warm fertilization group (n = 153), cold fertilization group (n = 133). i, BAT-d assessed as [total Hb] in the supraclavicular region in g,h. Biologically independent samples (b–i). Number of participants (n) is indicated on the graph. Data are mean ± s.e.m.; two-tailed P values by unpaired Student's t-test (b,e,f,i). Data are percentage; one-tailed P values by Fisher's exact test (c,d,g,h). Source data To address whether BAT activation by preconception environmental stress extends to the general population, we recruited 286 independent healthy male and female volunteers aged 20–78 years (Cohort 2). In this cohort, BAT density (BAT-d) was estimated noninvasively by measuring the total haemoglobin concentration ([total Hb]) in the supraclavicular region using near-infra-red time-resolved spectroscopy (NIR-TRS) (Fig. 1a). BAT-d measured by NIR-TRS exhibits a strong correlation with cold-induced FDG uptake by PET/CT, making it a reliable alternative index of BAT functionality29,30. We categorized the participants into high and low BAT-d groups based on the median of BAT-d (Fig. 1f and Extended Data Fig. 3a). Consistent with findings from Cohort 1, the season of birth did not affect the percentage of high BAT-d (Fig. 1g and Extended Data Fig. 3b,c) or quantitative BAT-d (Fig. 1i). In contrast, the percentage of high BAT-d was significantly greater in the cold fertilization group (56.4%) than in the warm fertilization group (44.4%, P = 0.029; Fig. 1h and Extended Data Fig. 3b,d). Additionally, we found a significant increase in BAT-d ([total Hb] at the supraclavicular BAT deposits), in the cold fertilization group compared with the warm fertilization group (P = 0.020; Fig. 1i). This increase in [total Hb] was specific to the supraclavicular BAT region and was not due to a general increase in blood flow because [total Hb] in other regions such as the abdominal subcutaneous white adipose tissue and the deltoid skeletal muscle remained consistent regardless of the season of birth or fertilization (Extended Data Fig. 3e,f). A disaggregated analysis for sex revealed an enhanced BAT-d in the cold fertilization group in male and female participants (Extended Data Fig. 3g). These results were consistent with those in Cohort 1 and support the idea that the metabolic fate of BAT in adulthood is predetermined by parental exposure to meteorological environments during the period around fertilization in healthy humans. It is widely recognized that cold-activated BAT has a crucial role in EE, especially in nonshivering cold-induced thermogenesis (CIT), which fluctuates seasonally in accordance with the recruitment of BAT31. We hypothesized that the intergenerational activation of BAT might influence CIT in a season-dependent manner. To test this, we analysed the resting EE at 27 °C and after 2-h cold exposure at 19 °C measured by indirect calorimetry in 42 young healthy males who underwent FDG-PET/CT31 (Cohort 3; Extended Data Fig. 4a–c). This test was conducted during both the summer (July to September) and winter (December to March) in a randomized crossover design. As expected, no notable difference in BAT activity was observed between the warm and cold birth seasons (Extended Data Fig. 4d, left). Whole-body EE adjusted for fat-free mass (FFM) at 27 °C and 19 °C and CIT were comparable between the warm and cold birth groups regardless of season of the measurements (Fig. 2a and Extended Data Fig. 4e,f). a, Whole-body resting EE and CIT of the warm (n = 23) and cold birth groups (n = 19) (Cohort 3) measured in winter. Left, resting EE adjusted for FFM at thermoneutral condition (27 °C) and after 2-h cold exposure (19 °C). Right, CIT. b, Whole-body resting EE and CIT of the warm (n = 14) and cold fertilization groups (n = 28) (Cohort 3) measured in winter. Resting EE adjusted for FFM at thermoneutral condition (27 °C) and after 2-h cold exposure (19 °C) (left). CIT (right). c, Postprandial changes in resting EE adjusted for FFM (left) and DIT calculated as incremental area under the curve (iAUC, right) for the warm (n = 10) and cold birth groups (n = 13) (Cohort 4). d, Postprandial changes in resting EE adjusted for FFM (left) and DIT calculated as iAUC (right) for the warm (n = 6) and cold fertilization groups (n = 17) (Cohort 4). Biologically independent samples (a–d). Data are mean ± s.e.m.; two-tailed P values by unpaired Student's t-test or by two-way repeated measures ANOVA (a,b and c,d, right) with post hoc unpaired Student's t-test (c,d left). Source data Conversely, BAT activity was significantly higher in the cold fertilization group than in the warm fertilization group (Extended Data Fig. 4d, right), consistent with findings observed in Cohorts 1 and 2. While there was no group difference in EE at 27 °C, the response of the adjusted EE to cold exposure seemed to be increased in the cold fertilization group compared with the warm fertilization group in the winter (Fig. 2b, left), but not in the summer (Extended Data Fig. 4g). Indeed, CIT was significantly higher in the cold fertilization group than in the warm fertilization group specifically in the winter (Fig. 2b, right) but not in the summer (Extended Data Fig. 4h). Given that neither shivering, as assessed by electromyography nor FDG uptake into the skeletal muscle is induced in our mild cold exposure protocol14,32, the observed increase in CIT is likely due to BAT activation. This aligns with the observation that BAT activity was positively correlated with CIT in the winter, but not in the summer (Extended Data Fig. 4i), FFM did not associate with CIT regardless of the season (Extended Data Fig. 4j). These findings suggest that BAT activation due to fertilization in the cold season enhances cold-induced BAT thermogenesis and contributes to seasonal cold adaptation in humans. We next examined the effects of the fertilization season on diet-induced thermogenesis (DIT), another component of BAT-associated adaptive thermogenesis33,34,35. In this study, whole-body EE was measured in 23 healthy adult males (Cohort 4; Extended Data Fig. 5a,b) by indirect calorimetry over a period of 2 h following the ingestion of a meal (Extended Data Fig. 5c,d)35. All DIT measurements were carried out in the winter months (December through March). We ensured that age and anthropometric parameters were comparable between the warm and cold birth groups and between the warm and cold fertilization groups. Postprandial thermogenesis and DIT, calculated as the incremental area under the curve, did not differ significantly between the warm and cold birth groups (Fig. 2c and Extended Data Fig. 5e). Increased BAT activity was observed in the cold fertilization group of Cohort 4 compared with the warm fertilization group (Extended Data Fig. 5b, right), as observed in Cohorts 1 and 3. It is noteworthy that postprandial thermogenesis and DIT were significantly higher in the cold fertilization group than in the warm fertilization group (Fig. 2d and Extended Data Fig. 5f). Finally, we asked whether fertilization in the cold season is sufficient to enhance total energy expenditure (TEE) under the free-living conditions in Cohort 5 (Extended Data Fig. 6a). To this end, we measured TEE using the doubly labelled water (DLW) method and physical activity levels using a validated triaxial accelerometer36,37. The DLW method is an accurate way of determining metabolic rate with the advantage that the participants need not be confined, allowing us to investigate TEE in free-living conditions. TEE assessed using DLW was associated with age, anthropometric parameters, physical activity levels and step count per day (Fig. 3a and Extended Data Fig. 6b). Multivariate regression analysis revealed that FFM and steps per day were significant predicting factors of TEE (model 1, R2 value = 0.794; Extended Data Fig. 6c). Of note, FFM- and step-independent TEE as residuals in model 1 was significantly higher in the cold fertilization group than in the warm fertilization group, whereas it was indistinguishable between the warm and cold birth groups (Extended Data Fig. 6d). Thus, adjusted TEE for FFM and steps was significantly higher in the cold fertilization group than in the warm fertilization group (Fig. 3b). A similar increase in adjusted TEE was found in a disaggregated analysis for sex (Extended Data Fig. 6e). Multivariate regression analysis revealed that the TEE-increasing effect of fertilization season was independent of body size- and physical activity-related parameters, including FFM and step count (Fig. 3c). Together, we demonstrate a critical role of the season of fertilization in adaptive CIT, DIT and TEE, suggesting that the pre-fertilization-origin activation of BAT is sufficient to modulate whole-body EE. a, Association of daily TEE measured by the DLW method with FFM, fat mass, step counts and physical activity level in Cohort 5 (n = 41). b, TEE adjusted for FFM and steps per day using an equation according to the multivariate regression analysis (model 1; Extended Data Fig. 6c) for predicting body size and physical activity-independent TEE of each participant. Warm birth group (n = 22) and cold birth group (n = 19) (left). Warm fertilization group (n = 20) and cold fertilization group (n = 21) (right). c, Univariate and multivariate regression analysis for estimating independent effects of birth and fertilization seasons on TEE. The warm and cold birth seasons were coded as 1 and 2, respectively. The warm and cold fertilization seasons were coded as 1 and 2, respectively. Model 2, R2 = 0.804, P < 0.001. Biologically independent samples (a–c). Pearson's correlation coefficient (r) and two-tailed P values (a). Data are mean ± s.e.m.; two-tailed P values by unpaired Student's t-test (b). Data are correlation coefficient by univariate Pearson's (for age, height, weight, FFM, fat mass, steps and physical activity) or Kendall's rank correlation analysis (for sex and seasons) (c, left). Error bars indicate 95% CIs. Data are unstandardized β (middle) and standardized β (right) by multivariate regression model with backward stepwise method (model 2); two-tailed P values (middle and right). Error bars indicate 95% CIs. Source data The above observations led us to hypothesize that fertilization in the cold season may reduce the risk of obesity and metabolic diseases in offspring by protecting against an age-related decline in BAT. Clinical cross-sectional studies demonstrated that BAT activity is inversely correlated with adiposity and blood glucose, preventing age-related obesity, insulin resistance and cardiovascular diseases7,8. In Cohort 1, the inverse association between BAT activity and BMI was relatively weak (Fig. 4a and Extended Data Fig. 7a), likely due to the younger age and lower adiposity levels among participants6,38. Conversely, more pronounced effects of BAT-d on obesity-related traits such as BMI, body fat content, visceral fat area and waist circumference were observed in Cohort 2, which included a wider range of ages and adiposity levels (Fig. 4b and Extended Data Fig. 7b). a, Associations of the season of fertilization and BAT activity with adiposity-related parameters in healthy young males (Cohort 1). b, Associations of the season of fertilization and BAT-d with adiposity-related parameters in the healthy participants with a wide range of ages (Cohort 2). SBP, systolic blood pressure; DBP, diastolic blood pressure. c, Impact of the seasons of birth and fertilization on adiposity-related parameters including BMI, body fat content, visceral fat area and waist circumference in b. d, Structural equation modelling for predicting the factors associated with BMI in a. e, Structural equation modelling for predicting the factors associated with BMI in b. Biologically independent samples (a–e). Pearson's (for age, BAT activity and BAT-d) or Kendall's rank correlation analysis (for seasons) and two-tailed P value by correlation analysis (a,b). Data are mean ± s.e.m.; two-tailed P value by unpaired Student's t-test. Numbers of participants (n) are indicated on the graph (c). Structural equation modelling: standardized β and two-tailed P values (d,e). NS, not significant. Source data Next, we investigated whether the fertilization season is associated with adiposity. In Cohort 1, with a limited-range of ages and adiposity, BMI and related parameters did not exhibit a direct correlation with either the birth season or the fertilization season (Fig. 4a and Extended Data Figs. 1c and 8a). In Cohort 2, however, we detected modest yet significant associations of the cold fertilization season with decreased BMI, visceral fat area and waist circumference (Fig. 4b). Similarly, BMI, body fat content, visceral fat area and waist circumference were significantly lower in the cold fertilization group than in the warm fertilization group (Fig. 4c). Conversely, the season of birth had a negligible effect on adiposity in both Cohort 1 and Cohort 2 (Fig. 4a,b). Additionally, parameters such as skeletal muscle mass and cardiovascular function, including blood pressure and heart rate, remained unaffected by either the birth or fertilization season (Extended Data Fig. 8b,c). To examine more deeply the intricate relationship between fertilization season, BAT and adiposity, we performed structural equation modelling based on the structural model hypothesized39. This analysis revealed that the fertilization season (coded as warm, 0 and cold, 1) positively correlated with BAT activity (Cohort 1: β = 0.145, P = 0.005, Fig. 4d; Cohort 2: β = 0.132, P = 0.022, Fig. 4e), which in turn negatively correlated with BMI (Cohort 1: β = −0.175, P < 0.001; Cohort 2: β = −0.547, P < 0.001). The direct association between the fertilization season and BMI, however, was not statistically significant (Cohort 1: β = −0.022, P = 0.671; Cohort 2: β = −0.041, P = 0.365). Based on these findings, we concluded that a decrease in BMI associated with the cold fertilization season is due to increased BAT activity. Meteorological parameters, including temperature, vary seasonally, as depicted in Extended Data Fig. 9, and some of these parameters, along with temperature, can modulate BAT activity40,41. For example, studies in rodents demonstrated that photoperiod regulates BAT thermogenesis via the sympathetic nervous system or μ-opioid receptor signalling42,43. To pinpoint the environmental factor responsible for the intergenerational BAT activation, we performed an unbiased spatiotemporal meteorological analysis. This analysis involved examining associations between the participant's BAT activity and environmental parameters before, during, and after pregnancy periods within their specific region of residence (Fig. 5a). a, Schematic of the study design for the meteorological survey and the definition of pregnancy periods. The pregnancy period was divided into five periods: preconception (−12 to −9 months), the first trimester (−9 to −6 months), second trimester (−6 to −3 months), third trimester (−3 to 0 months) and postpartum (0 to 3 months). b, Schematic showing the extraction of meteorological data for pregnancy periods from Japan created by the JMA, the NARO and the NAOJ. Data were obtained for birth and fertilization regions. c, Multivariate logistic regression using the backward stepwise method to predict BAT activity in young male volunteers (n = 93, model 1). Model 1 was adjusted for age, BMI, medical history and lifestyle factors (smoking and shift work). Variables included BAT activity (binary: 1 or 0), age and BMI: (the tertile values: 1, 2 or 3), low birth weight (yes, 1 and no, 0), smoking status (never, former, current: 1, 2, 3) and shift work (never, former, current: 1, 2, 3). d, Independent effects of diurnal temperature variation on BAT activity in c (model 2). Diurnal variation, calculated as the difference between dairy maximum and minimum temperatures, was added alongside daily mean temperature and other meteorological parameters. Model 2 adjustments were identical to model 1. e, Participants were categorized by seasonal birth and fertilization conditions: (1) warm birth/warm fertilization (n = 77), (2) warm birth/cold fertilization (n = 111), (3) cold birth/warm fertilization (n = 82) and (4) cold birth and cold fertilization (n = 86). f,g, Combined effects of the seasons of birth and fertilization on BAT prevalence (f) and activity (g). Numbers of participants with active BAT/total participants are indicated on the bars. Biologically independent samples (c–g). Data are adjusted ORs with 95% CIs as error bars: two-tailed P values by multivariate logistic regression (c,d); percentage: one-tailed P values by Fisher's exact test (f); mean ± s.e.m.; two-tailed P values by unpaired Student's t-test (g). Source data A total of 93 participants in Cohort 1 completed a questionnaire regarding their regions of birth and conception, their lifestyles and meteorological questionnaire survey. We collected meteorological parameters, including outdoor temperature, humidity, precipitation, sunshine duration, daytime length and atmospheric pressure, at the region residence during five pregnancy periods: before conception (−12 to −9 months from the birth), the first trimester (−9 to −6 months), the second trimester (−6 to −3 months), the third trimester (−3 to 0 months) and after delivery (0 to 3 months) (Fig. 5a,b). A multivariate logistic regression analysis with adjustments for age, BMI, smoking status and shift work status (referred to as model 1) revealed that the daily mean outdoor temperature before fertilization correlated inversely with BAT activity (adjusted OR = 0.335, 95% CI 0.138−0.809, P = 0.015; Fig. 5c), while humidity, precipitation, sunshine duration and daytime length showed no significant association with BAT activity. Additionally, we discovered a positive association between BAT activity and daily maximum temperature (adjusted OR = 3.033, 95% CI 1.27−7.25, P = 0.013), which contradicted the negative association with the daily mean temperature. We hypothesize that diurnal temperature variation might serve as a latent environmental stimulus for activating BAT in the offspring. To test this, we calculated the diurnal range of temperature and incorporated it into model 1 as an independent variable (referred to as model 2). Notably, this parameter emerged as the most significant determining factor of BAT activity (adjusted OR = 1.61, 95% CI 1.028−2.519, P = 0.037; Fig. 5d). A similar association was found when diurnal temperature gap between daily maximum and mean temperature was incorporated in to the multivariate regression model (model 3; Extended Data Fig. 10a). These results suggest exposure to a lower outdoor temperature and larger diurnal temperature variation before conception preserves BAT activity of the offspring in adulthood. Furthermore, the multivariate regression model revealed no association of BAT activity with outdoor temperature or its diurnal variation in the first, second and third trimesters (Fig. 5c,d and Extended Data Fig. 10a), suggesting a negligible effect of maternal thermal stress during gestation, consistent with earlier studies in mice28,43. We also observed an inverse association between the daily mean outdoor temperature and diurnal temperature fluctuation after delivery and BAT activity (Fig. 5c and Extended Data Fig. 10a). We then tested the potential synergistic effect of thermal stress before conception and after delivery on BAT. To this end, we categorized the participants into four groups: (1) those with warm birth and warm fertilization seasons, (2) those with warm birth and cold fertilization seasons, (3) those with cold birth and warm fertilization seasons, and (4) those with cold birth and cold fertilization seasons (Fig. 5e). Increases in the BAT prevalence and activity by the cold fertilization season were clearly confirmed in the cold birth group whereas they were only marginal in the warm birth group (Fig. 5f,g). It is possible that cold exposure after delivery enhances the BAT-activating effect of preconception cold exposure although this requires further investigation. However, thermal exposure before conception is likely the primary stimulus because a clear linear-by-linear association between diurnal temperature gap and BAT prevalence was detected specifically in a period before conception (Extended Data Fig. 10b). In summary, the spatiotemporal meteorological analysis revealed that a low outdoor temperature and a large diurnal temperature variation just before conception preserves BAT activity and energy homeostasis in human offspring (Fig. 6). Preconception exposure to low outdoor temperature and temperature gap affects offspring's metabolic phenotype, promoting higher EE in humans. Our findings propose a conceptional theory, named PfOHaD. This concept suggests that environmental factors, such as temperature exposure before conception, can programme physiological traits in offspring, potentially influencing their health outcomes across generations. Our study demonstrated that the season of fertilization significantly influences BAT development and metabolic health in adulthood. Utilizing healthy volunteers and employing three distinct methods (FDG-PET/CT, NIR-TRS and DLW), we observed a potential link between EE and the season of fertilization, which may be mediated by BAT activity. These findings extend the work by Sun et al.28, who reported that individuals conceived during colder months were 3.2% more likely to possess active BAT, whereas those conceived in warmer months were more likely to lack active BAT. They suggested that the season of conception is linked to BAT development in humans, proposing an intergenerational activation of BAT through paternal lineage, potentially involving sperm DNA methylation as demonstrated in mouse models. Incorporating meteorological analyses, we found that not only outdoor temperature but also diurnal temperature variations impact BAT activity, with effects observed based on the season of fertilization rather than birth season. These findings support and expand the theory of Developmental Origins of Health and Disease (DOHaD) to encompass the concept of Pre-fertilization Origins of Health and Disease (PfOHaD), as discussed in later sections. A major strength of our study is the thorough assessment of BAT using the gold-standard method and a large sample size of healthy participants. Prospective studies demonstrated that BAT remains metabolically inactive in warm conditions regardless of its maximal thermogenic capacity5,32,44,45. Moreover, BAT activity varies seasonally depending on age, sex and adiposity5,8,40,46. These factors impose a major limitation on retrospective assessment of BAT using clinical scans. In the present study, we ensured a sensitive evaluation of BAT functionality with season-matched FDG-PET/CT and acute nonshivering cold exposure. This analysis included over 350 young, lean male participants to minimize potential fluctuations in BAT activity. While FDG-PET may underestimate BAT activity in conditions such as insulin resistance47, our all participants of Cohort 1 were healthy individuals. Our well-designed approach and the largest sample size in this field, allow us to certify the intergenerational influence of cold stress on BAT activity in humans. Of note, we validated the fertilization season-specific activation of BAT in an independent population of Cohort 2 with no discernible effect of the birth season. Despite a wide range of ages and adiposity in Cohort 2 and including both males and females, multivariate regression revealed that BAT activation by the cold fertilization season is independent of age, sex and adiposity. Moreover, the difference in the BAT prevalence between the warm and cold fertilization groups was 11.9% for Cohort 2, consistent with Cohort 1 (14.6%). Notably, these differences were four-times higher than those reported in the previous retrospective analysis of oncology scans (3.2%)28. Our results demonstrate the extent to which preconception seasonal acclimatization enhances BAT activity in offspring. Previous studies demonstrated BAT's role in nonshivering adaptive thermogenesis (CIT and DIT)12,34,35,48. Our study is the first to show that preconception environmental exposure enhances whole-body EE and adaptive thermogenesis due to a significant increase in BAT activity. CIT for the cold fertilization group was 1.5-times higher than the warm group. In contrast, resting EE at 27 °C was unaffected by the fertilization season, as BAT remains inactive in thermoneutral conditions. The impact of the fertilization season on CIT was negligible in the summer, when BAT activity is low31. These results suggest that preconception cold exposure is sufficient to increase adaptive thermogenesis and whole-body EE. Notably, TEE under free-living conditions increased by ~5.8% in the cold fertilization group compared with the warm group, indicating that intergenerational inheritance of cold adaptation enhances whole-body EE in humans. Future study employing 15O-O2 and 11C-acetate PET/CT is required for validating the contribution of BAT to intergenerational control of whole-body EE. Fertilization during the cold season was linked to a lower BMI in Cohort 2, which encompassed a wider range of age and adiposity levels. Structural equation model suggested that the BMI-decreasing effect is mediated by BAT activation. Given the absence of a significant impact of the fertilization season on BMI in young lean individuals (Cohort 1), we propose that the beneficial metabolic effect of preconception cold exposure is greater in middle-aged and older populations. Consistent with this notion, a cross-sectional study involving over 4,500 middle-aged males reported that the prevalence of metabolic syndrome is high in those born in the spring (with an estimated summer fertilization season) compared with those born in the fall (with an estimated winter fertilization season)49. Similar trends were reported by a large cohort study that included male and female participants50,51. The current study highlights the need of investigating the hypothesis that global warming may be contributing to disruptions in energy homeostasis and the ongoing obesity pandemic. Together, our present findings suggest a crucial role of intergenerational regulation of BAT in the systemic energy homeostasis, reducing the propensity for age-associated metabolic diseases. Our findings align with earlier studies reporting protective roles of BAT against insulin resistance and cardiovascular diseases7,38,40. The mechanisms of intergenerational activation of human BAT have remained unclear because the key meteorological factors remained undetermined. Our unique spatiotemporal meteorological analysis, however, identified the daily mean outdoor temperature before conception as a significant determinant of BAT metabolic fate in adult offspring. This finding is compatible with findings in mice28. Other parameters, such as daytime length, sunshine duration, humidity and precipitation, before conception were not associated with BAT activity. Multivariate logistic regression suggested that diurnal temperature variations serve as a novel meteorological factor that mediates BAT activation. Although the mechanisms remain unclear, the sympathetic nervous system (SNS) may be involved in this temperature gap-induced activation. For example, the cold pressor test (cold water immersion of the limbs) increases SNS activity in humans without altering core body temperature52. Further investigations are needed to confirm whether the SNS plays a role in passing on BAT activity to the next generation in humans. Potential factors that may influence the intergenerational activation of BAT include individual differences in dietary and behavioural pattern, genetic variants, and other unmeasurable variables such as living indoor temperature and gut microbiota composition24,53,54,55,56,57,58,59,60. The use of pharmacological agents such as adrenomimetics may also confound the association of preconception thermal stress with BAT44,61,62,63. We note, however, that all our participants were healthy individuals who did not regularly take medications, and neither smoking history nor shift work status influenced the BAT activation. A notable limitation of our study is the use of a fixed cold exposure at 19 °C to assess BAT activity with FDG-PET/CT. We cannot rule out the possibility that our fixed cold exposure might be insufficient for some participants with low cold perception, resulting in low BAT activity. An alternative approach would be FDG-PET/CT with personalized cold exposure protocol64. The use of only FDG as a radiotracer is also a limitation because FDG uptake does not directly reflect total heat production in BAT and its anatomical presence47, although it is proportional to nonshivering CIT. However, fixed protocols like ours have been recognized as suitable for evaluating BAT's thermogenic responsiveness to a certain stimulus, which is one of the most physiologically important readouts64,65. Nevertheless, our findings need to be validated by future studies employing PET/CT with various tracers in combination with personalized cold protocols13,61,64,65. Moreover, our correlational results do not exclude possibility that other tissues, including skeletal muscle66,67, contribute to the intergenerational cold adaptation and metabolic improvement. Additional investigations are required to establish BAT as a causative driver of metabolic improvements due to pre-fertilization cold exposure. Another limitation of this study is its geographically focus on Japan. Future studies should test the effects of different geographic regions of living and races of individuals on the intergenerational activation of BAT. In addition, our meteorological approach faces challenges in determining whether the intergenerational regulation of BAT originates from the paternal lineage, as reported in mice28. In this regard, two independent study groups reported that maternal cold exposure does not activate BAT in mice28,43. We also emphasize that no meteorological parameter during the first, second and third trimesters correlated with BAT activity, suggesting minimal effects of maternal lineage during gestation. Although it may not be feasible to experimentally validate whether it is paternal lineage in humans, alternative approaches may involve investigations of cold-induced epigenetic changes in human sperm68,69, as discussed in the below paragraph. It seems likely that the intergenerational control of BAT by preconception cold exposure is linked to the paternal lineage. In future studies, it would be useful to identify the molecular mechanisms underlying intergenerational epigenetic inheritance of cold exposure and to examine the effect of cold exposure on sperm, ovum, fertilized eggs and embryos in humans. Earlier studies in small rodents suggested that certain molecular mechanisms in sperm govern the intergenerational inheritance of paternal metabolic stress68,69. First, a previous DNA pyrosequencing study revealed that paternal preconception cold exposure induces alterations of DNA methylation in mouse sperm28. The specific genes or sites targeted by cold-induced DNA methylation, as well as their causal link to the BAT activation remain undetermined. Second, although sperm chromatin undergoes massive epigenetic reprogramming through histone–protamine exchange, minimal histones (~1% in mice and ~10% in humans) are retained in mature sperm70. The retained histones carry epigenetic marks, for example methylation, which are transferred to the embryo and play a role in intergenerational physiological adaptation71,72,73. Third, transfer RNA-derived small RNAs (tsRNA) have the potential to be transmitted to the zygote and are proposed as a molecule responsible for germline epigenetic transmission27,74,75,76. Future studies should investigate the roles of these mechanisms in the intergenerational inheritance of cold exposure. Together, these findings provide evidence of a discernible impact of preconception cold exposure on BAT metabolic fate, adaptive thermogenesis and systemic energy homeostasis in human offspring. Our findings indicate a perspective beyond the DOHaD theory, which acknowledges that environmental stress, for example poor nutritional conditions, during pregnancy or lactation triggers predictive adaptation during embryonic and postnatal development via the maternal lineage77. Because the intergenerational activation of BAT is initiated before fertilization, we propose a conceptional theory, named PfOHaD, which can theoretically originate from both maternal and paternal lineages. The PfOHaD-based activation of BAT may be a sophisticated predictive cold adaptation through specific mechanisms, enabling offspring to survive despite cold climates and thereby contributing to species conservation. Understanding the molecular mechanisms of epigenetic transmission between generations, as well as how cellular memories stored in specific cell types operate, will open research opportunities to develop therapeutic approaches aimed at attenuating an ageing-associated decline in BAT activity and achieving cardiometabolic benefits in humans. Healthy adult volunteers were provided information about the study and gave their written informed consent for participation in the FDG-PET/CT examination and the meteorological questionnaire survey. The FDG-PET/CT and NIR-TRS data obtained in our previous studies8,30 were enrolled in the analysis by obtaining the written informed consent or through an opt-out process. The data of the CIT, DIT, and TEE obtained in our previous studies31,35,37 were enrolled in this study through an opt-out process. Inclusion criteria included age (Cohorts 1, 3 and 4, 18 years and older8,31,35; Cohort 2, 20 years and older30 and Cohort 5, 3–6 years37). Exclusion criteria included individuals with metabolic diseases, those who regularly take medications for diabetes, hyperlipidaemia or hypertension, heavy smokers (>21 cigarettes per day), those drinking more than the average amount of alcohol (30 g alcohol per day or more), those who are pregnant or breastfeeding, and those who are considered unsuitable for the study by investigators (Supplementary Table 1 and Supplementary Fig. 1a–f). In addition, only male participants aged 18–29 years old were included in the analysis for Cohort 1 to minimize the confound effects of age and sex on the results, whereas both sexes were included in Cohorts 2 and 5 to test whether our findings can be generalized regardless of sex. The written informed consent for participation was obtained from 242 participants of Cohort 1 (68.0%) and all 268 participants of Cohort 2 (100%). Data of the FDG-PET/CT examination from the remaining 114 participants of Cohort 1 (32.0%) and data of CIT/DIT obtained in our previous studies were utilized under an opt-out basis. CIT was measured both in summer and in winter in a randomized crossover design31, whereas the other experiments were performed in observational study designs with no randomization. The FDG-PET/CT, NIR-TRS, CIT, DIT measurements and the DLW examination as well as measurements of anthropometric parameters were performed by experienced physicians/radiologists/investigators who were blinded to the experimental group and study hypothesis. Meteorological parameters were obtained by two research assistants who were blinded to the experimental groups. The study protocols were approved by the Institutional Research Ethics Review Boards of the University of Tokyo (23-585) and Tohoku University (35632). The trial was registered at http://www.umin.ac.jp/ctr/ (UMIN000050690). The primary outcomes were BAT activity/density, EE and adiposity (BMI, visceral fat area, waist circumference) and secondary outcomes included FFM, fat mass, heart rate and blood pressure. Cold-activated BAT was assessed by FDG-PET/CT following standardized nonshivering cold exposure, as reported previously8,12. All FDG-PET/CT examinations were performed in the winter (December through March). After fasting for ~12 h, participants remained in a room at 19 °C for 2 h. The participants received 18F-FDG (1.7 MBq kg−1 body weight) intravenously after 1 h of cold exposure and remained in the same cold conditions for another hour. PET/CT was performed using a PET/CT system (Aquiduo, Toshiba Medical Systems), Biograph 16 (Siemens Medical Solutions) or Discovery PET/CT 600 (GE Healthcare). Cold-induced BAT activity was quantified by the standardized uptake value (SUV) of FDG in the supraclavicular adipose deposits with Hounsfield Units from −300 to −10. On the basis of the presence of detectable BAT activity greater than SUV 2.0, participants were divided into high and low BAT groups8,12. Experienced investigators monitored participant's condition during cold exposure and no adverse effect of cold exposure was reported. The participants relaxed in a room at 23–27 °C and 3-cm probes were placed at the skin of the supraclavicular region. Total haemoglobin concentration ([total Hb]) in the supraclavicular region was measured based on the optical properties evaluated by NIR-TRS29,30,78. Because the abundance of capillaries in BAT helps to distinguish it from other tissues, including white adipose tissue, the supraclavicular [total Hb] is an indicator of BAT-d, which is correlative to SUV by FDG-PET/CT. NIR-TRS data were extracted every 10 s and averaged over 1 min using a NIR-TRS system (TRS-20; Hamamatsu Photonics K.K.). The obtained NIR-TRS parameters were adjusted for the thickness of subcutaneous fat in the region by B-mode ultrasound (Vscan Dual Probe; GE Vingmed Ultrasound AS). Based on the median value of the supraclavicular [total Hb], participants were divided into high and low BAT-d groups. As control regions, [total Hb] in the deltoid skeletal muscle and in the abdominal subcutaneous adipose tissue were measured. BMI was calculated as the body weight in kilograms divided by the square of the height in metres (kg m−2) and the per cent of body fat was estimated using the multifrequency bioelectric impedance method (InBody 320 and 720 Body Composition Analyser; Biospace) or a dual-energy X-ray absorptiometry scan (Lunar Prodigy; GE Healthcare). In concurrence with FDG-PET/CT, the visceral and subcutaneous fat areas at the abdominal level of L4–L5 were estimated from the CT images. The visceral fat area of participants undergoing the NIR-TRS examination was estimated using a bioelectrical impedance analysis (EW-FA90; Panasonic). Waist circumference was measured using a flexible narrow, nonstretchable tape. Systolic blood pressure, diastolic blood pressure, and heart rate were measured by an automated sphygmomanometer (HBP-9020; Omron Healthcare). The FFM of participants of the DLW procedure was calculated from the total body water (TBW) using the hydration factor by the International Atomic Energy Agency36,37. Fat mass was calculated by subtracting the FFM (kg) from the body weight. Whole-body EE and CIT were measured by indirect calorimetry in the summer (July to September) and winter (December to March) in a randomized crossover design31. After fasting for ~12 h, participants relaxed in a sitting position in a room at 27 °C for at least 30 min. Oxygen consumption (VO2) and carbon dioxide production (VCO2) were then recorded for 20–30 min using a respiratory gas analyser connected to a ventilated hood (AR-1, Arco System). After 2 h cold exposure at 19 °C, VO2 and VCO2 were recorded again. The stable value of the last 10-min period was used to calculate EE. Whole-body EE was adjusted for FFM, the major component of the individual variation of EE. CIT was calculated as the difference in the adjusted EE between before and after cold exposure. Whole-body EE before and after meal ingestion was measured using a respiratory gas analyser (AR-1, Arco System) in winter (December to March)35. After fasting for ~12 h, participants relaxed on a bed in a room at 27 °C, and VO2 and VCO2 were recorded for ~30 min. The participants were then given a test meal with a total energy of 7.9 kcal kg−1 body weight in 10 min. The energy ratio of the meal was 11% protein, 38% fat and 51% carbohydrate. After 15, 45, 75 and 105 min, VO2 and VCO2 were measured for 20 min. The stable value in the last 10-min period was used to calculate the EE. Whole-body EE was adjusted for FFM. Postprandial thermogenesis was calculated as the change of adjusted EE from baseline and the incremental area under the curve of postprandial thermogenesis over 2 h was calculated for estimating DIT. Daily TEE was measured over 1 week using the DLW procedure, the gold-standard method to determine whole-body EE under free-living conditions36,37. All DLW procedures were performed in the winter (December). Upon accessing the preschool, a urine specimen was collected to measure the baseline 2H and 18O before administering DLW (day 0). Each participant was given a beverage containing a premixed dose of ~0.12 g kg−1 estimated TBW of 2H2O (99.8 at.%, Taiyo Nippon Sanso) and 2.5 g kg−1 estimated TBW of H218O (10.0 at.%, Taiyo Nippon Sanso). The urine samples were then collected on the following day (day 1) and on day 8. The urine specimens were analysed using isotope ratio mass spectrometry (Hydra 20–20; Sercon). The dilution space of 2H and 18O (Nd and No, respectively) was determined by dividing the amount of the given tracer using the intercept method in two specimens from day 0 and two samples from the days 1 and 8. The TBW was calculated as the mean of Nd (mol) divided by 1.043 and No (mol) divided by 1.007 (ref. 79). Carbon dioxide production rates (rCO2, mol d−1) were calculated using the following equation: rCO2 (mol d−1) = 0.4554 × TBW (mol) × (1.007 × ko − 1.043 × kd), where ko and kd represent the 18O and 2H elimination rates per day, respectively. TEE was determined using a modified Wier equation based on rCO2 and 24-h respiratory quotient (RQ) estimated as 0.87 (ref. 37): TEE (kcal d−1) = 1.106 × rCO2 (l d−1) + 3.94 × (rCO2/RQ). In concurrence with the DLW procedure for 1 week, the participants were asked to wear a previously validated triaxial accelerometer (Actimarker, Panasonic) over the waist80 from morning till night, except during bathing and bedtime. The obtained data during the experimental period were used for calculating daily mean steps and daily mean physical activity levels. Day of fertilization was estimated as the day 266 days before the due date (day of birth). To define seasons of birth and fertilization, the year was divided into the cold season (1 January through 15 April and 17 October through 31 December) and warm season (16 April through 16 October) by splitting spring and autumn. To examine the effects of meteorological exposure before, during and after pregnancy on BAT of the offspring, five pregnancy periods were defined based on the days of birth and fertilization; before conception (−12 to −9 months from the birth), the first trimester (−9 to −6 months), the second trimester (−6 to −3 months), the third trimester (−3 to 0 months) and after delivery (0–3 months). Meteorological parameters in these periods were obtained from the meteorological and climatic big databases for Japan: the Agro-Meteorological Grid Square Data by the National Agriculture and Food Research Organization (NARO) for outdoor temperature, its diurnal variation, precipitation and sunshine duration81; the Japan Meteorological Agency (JMA) database for humidity and atmospheric pressure; the National Astronomical Observatory of Japan (NAOJ) database for sunrise and sunset times for 2012–2020 to calculate the daytime length for each calendar day. Data are expressed as the mean with s.e.m. or the proportion unless otherwise specified. Statistical analysis was carried out using a statistical software package (IBM SPSS Statistics v.29.0 and Amos 29.0, IBM Japan; Microsoft Office Excel 2016, Microsoft Japan). The difference in continuous variables between two experimental groups was analysed using an unpaired Student's t-test. The effect of the birth or fertilization seasons on the BAT prevalence, as well as differences in the proportion of female participants between the experimental groups, was analysed by Fisher's exact test or linear-by-linear association chi-squared test. Subgroup analysis for sex was performed in Cohorts 2 and 5 to test whether intergenerational effect of seasons of birth and fertilization was consistent across males and females. Simple correlations were assessed using a univariate linear regression analysis and Pearson's or Kendall's correlation coefficient. Whole-body EE measured by indirect calorimetry was adjusted for FFM using a linear regression equation31. The adjusted EE before and after 2-h cold exposure was compared using a paired t-test with three outliers by the Smirnov–Grubbs' test removed31. Postprandial EE over 2 h with one noncompliance of fasting and one outlier removed35 was tested by two-way repeated measures analysis of variance (ANOVA) on a within-subject factor (time) and a between-subject factor (season), with a post hoc unpaired t-test performed when the interaction effect (time × season) was statistically significant. TEE was adjusted for FFM and step counts by means of the stepwise multivariate regression model to estimate body size- and physical activity-independent TEE. The magnitude of the independent associations between BAT and the birth/fertilization seasons was estimated by calculating ORs and 95% CIs using a multivariate logistic regression model with adjustments for age and BMI. The association between BAT and meteorological parameters were estimated by means of multivariate logistic regression models with the backward method for the adjustment for age, BMI, smoking status, shift work status and a medical history of low birth weight. Direct and indirect, BAT-mediated inferences of the birth/fertilization seasons on BMI were estimated by employing structural equation model39. No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publications31,35,82. A P value <0.05 was considered statistically significant. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Full individual data are not publicly available due to them containing information that could compromise research participant privacy or consent. 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Biosphere 16, 71–79 (2016). Article Google Scholar Fuse, S. et al. Brown adipose tissue density measured by near-infrared time-resolved spectroscopy in Japanese, across a wide age range. J. Biomed. Opt. 23, 1–9 (2018). Article PubMed Google Scholar Download references This work was supported by the Japan Agency for Medical Research and Development (JP20gm1310007 to J.S., Y.M. and T.Y.), the Japan Science and Technology Agency (JPMJFR2014 to T.Y. and JPMJPF2013 to H.N.), the JSPS KAKENHI (JP21K08548 and JP20K22647 to T.Y.; JP16H06390, JP20H04835, JP20K21747, JP21H04826, JP22K18411 and JP24H00065 to J.S.; and JP22590227 and JP18K11013 to M.S.), the SECOM Science and Technology Foundation to J.S. and the Naito Foundation to T.Y. We thank Y. Yamamoto and T. Yamaoka for technical assistance in meteorological survey and acquiring data and M. Yoshio and Y. Ono for secretary assistance. These authors contributed equally: Takeshi Yoneshiro, Mami Matsushita, Sayuri Fuse-Hamaoka. These authors jointly supervised this work: Takeshi Yoneshiro, Takafumi Hamaoka, Juro Sakai, Masayuki Saito. Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan Takeshi Yoneshiro, Makoto Arai, Yuchen Wei, Yoshihiro Matsumura & Juro Sakai Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan Takeshi Yoneshiro, Makoto Arai, Yuchen Wei, Yoshihiro Matsumura & Juro Sakai Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Sapporo, Japan Mami Matsushita & Masayuki Saito Department of Sports Medicine for Health Promotion, Tokyo Medical University, Tokyo, Japan Sayuri Fuse-Hamaoka, Miyuki Kuroiwa, Yuko Kurosawa & Takafumi Hamaoka Sports and Health Sciences, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan Yosuke Yamada Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, Japan Yosuke Yamada Academic-Industrial Joint Laboratory for Renewable Energy, RCAST, The University of Tokyo, Tokyo, Japan Makoto Iida Climate Science Research Laboratory, RCAST, The University of Tokyo, Tokyo, Japan Kenichi Kuma & Hisashi Nakamura LSI Sapporo Clinic, Sapporo, Japan Toshimitsu Kameya & Tomoya Harada Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan Yoshihiro Matsumura Division of Nutriomics and Oncology, RCAST, The University of Tokyo, Tokyo, Japan Tsuyoshi Osawa Faculty of Education, Bukkyo University, Kyoto, Japan Yoshiko Aoki Faculty of Health and Medical Sciences, Kyoto University of Advanced Science, Kyoto, Japan Yoshiko Aoki Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan Masayuki Saito You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar You can also search for this author inPubMed Google Scholar T.Y., M.M., T.K., T. Harada and M.S. carried out FDG-PET/CT. S.F.H., M.K. and Y.K. performed NIR-TRS. T.Y. and S.F.H. performed the meteorological survey and statistical analysis with technical assistance from M.A., Y.W., M.I., K.K., Y.M., T.O. and H.N. Y.Y. and Y.A. performed the DLW experiment. T.Y., T. Hamaoka, J.S. and M.S. conceived the research and wrote the paper. All authors approved the final version of the paper. Correspondence to Takeshi Yoneshiro, Takafumi Hamaoka, Juro Sakai or Masayuki Saito. The authors declare no competing interests. Nature Metabolism thanks Raffaele Teperino and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Revati Dewal, Jean Nakhle in collaboration with the Nature Metabolism team. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. (a) Participant profiles in the high (n = 259) and low (n = 97) BAT groups of Cohort 1. BAT activity was evaluated as SUV of FDG assessed by the FDG-PET/CT examination combined with acute cold exposure. Number of males/females in parentheses. (b) Climatological annual cycle of outdoor temperature in northern (Sapporo, latitude 43˚N), eastern (Tokyo, 36˚N), and western areas (Kagoshima, 31˚N) of Japan. Daily mean outdoor temperature for 11 years (2010–2020) was obtained from the JMA database and 11-day moving average was calculated for each calendar day. For the sake of simplicity, the year was divided into the cold season (January 1st – April 15th, and October 17th – December 31st) and warm season (April 16th – October 16th). (c) Participant profiles of the warm (n = 188) and cold (n = 168) birth groups and the warm (n = 159) and cold (n = 197) fertilization groups in Cohort 1. (d) A plot of the place of birth/fertilization of the participants of Cohort 1 who completed the birthplace survey (n = 237). The pie chart represents distribution of the participants to the eight major regions of Japan. (a, c, d) Biologically independent samples. Data are mean ± s.e.m.; two-tailed P values by unpaired Student's t-test. Source data (a) Fluctuation of the prevalence of cold-activated BAT by month of birth. Numbers of participants with high and low BAT are indicated on the graph. (b) Fluctuation of the prevalence of cold-activated BAT by month of fertilization. Number of participants with high and low BAT are indicated on the graph. (c) Logistic regression analysis of BAT activity in Cohort 1. (d) Percentage of detection of cold-induced BAT in various regions in high BAT subjects (n = 259). (e) Percentage of the number of depots with active BAT in high BAT subjects (n = 259). (f) Effect of birth season on the number of active BAT depots in Cohort 1 (n = 356). (g) Effects of fertilization season on the number of active BAT depots in Cohort 1 (n = 356). (a-g) Biologically independent participants. (a, b, d-g) Data are percentage, and one-tailed P values by Fisher's exact test (f, g). (c) Multivariate logistic regression analysis: adjusted odds ratios (ORs) with 95% confidence intervals (CIs) as error bars and two-tailed P values. * P < 0.05, ** P < 0.01. High BAT coded as 1 and low BAT coded as 0, as the dependent variable. Age: ≤ 22 years old, 23 years old, and ≥ 24 years old were coded as 1, 2, and 3, respectively. BMI: ≤ 20.3 kg/m2, 20.4 to 22.0 kg/m2, and > 22.0 kg/m2 were coded as 1, 2, and 3, respectively. The warm season and cold season of the birth and fertilization are coded as 0 and 1, respectively. Source data (a) Participant profiles of Cohort 2. BAT-d was evaluated using NIR-TRS. Participants were divided into two groups: high and low BAT-d groups. All participants: n = 286 except visceral fat area (n = 264), systolic (SBP, n = 282), and diastolic blood pressure (DBP, n = 282). High BAT-d: n = 143 except visceral fat area (n = 124), SBP (n = 140), and DBP (n = 140). Low BAT: n = 143 except visceral fat area (n = 140), SBP (n = 142), and DBP (n = 142). Number of males/females shown in parentheses. (b) Participant profiles of the warm (n = 144) and cold (n = 142) birth groups and the warm (n = 153) and cold (n = 133) fertilization groups in Cohort 2. (c) Fluctuation of the percentage of participants with high BAT-d by month of birth. Number of participants with high and low BAT-d are indicated on the graph. (d) Fluctuation of the percentage of participants with high BAT-d by month of fertilization. Number of participants with high and low BAT-d are indicated on the graph. (e) Total haemoglobin concentration, [total Hb], in the abdominal subcutaneous white adipose tissue: Comparisons between the warm (n = 136) and cold (n = 138) birth groups and between the warm (n = 147) and cold (n = 127) fertilization groups. (f) The [total Hb] in the deltoid skeletal muscle: Comparisons between the warm birth (n = 79) and cold birth (n = 77) groups and between the warm fertilization (n = 86) and cold fertilization (n = 70) groups. (g) A disaggregated analysis of BAT-d at the supraclavicular region for sex. Left: male, n = 108. Right: female, n = 178. (a-g) Biologically independent participants. Data are mean ± s.e.m.; two-tailed P values (a, b, e, f) or one-tailed P values (g) by unpaired Student's t-test. Percentage of sex in (a, b); one-tailed P values by Fisher's exact test. Source data (a) Schematic illustration of the crossover study design to measure CIT in summer (Jul., Aug., Sep.) and winter (Dec., Jan., Feb., Mar.) in Cohort 3 (n = 42). (b) Correlations between fat-free mass (FFM) and whole-body energy expenditure (EE) at thermoneutral 27°C and after cold exposure at 19°C for 2 hr in a. Left, EE measured in summer. Right, EE measured in winter. (c) Participant profile of the warm birth and cold birth groups and the warm fertilization and cold fertilization groups of Cohort 3. (d) BAT activity as the SUV of FDG for subjects in c. Left, the warm birth group (n = 23) and cold birth group (n = 19). Right, the warm fertilization group (n = 14) and cold fertilization group (n = 28). (e) Whole-body EE adjusted for FFM of the warm and cold birth groups at thermoneutral condition (27°C) and after 2-hr cold exposure (19°C) measured in summer. Warm birth group (n = 23); cold birth group (n = 19). (f) CIT of the warm and cold birth groups measured in summer in e. (g) Whole-body EE adjusted for FFM of the warm and cold fertilization groups at thermoneutral condition (27°C) and after 2-hr cold exposure (19°C) measured in summer. Warm fertilization group (n = 14); cold fertilization group (n = 28). (h) CIT of the warm and cold fertilization groups measured in summer in g. (i) Correlations of BAT activity with CIT measured in summer (left) and in winter (right). (j) Correlations of FFM with CIT measured in summer (left) and in winter (right). (b-j) Biologically independent samples. (c-h) Data are mean ± s.e.m.; two-tailed P values by unpaired Student's t-test. (b, i, j) Pearson's correlation coefficient (r) and two-tailed P values. Source data (a) Participant profiles of the warm birth and cold birth groups and the warm fertilization and cold fertilization groups in Cohort 4 (n = 23). (b) BAT activity as SUV of FDG for subjects who participated in DIT measurement (Cohort 4). Left, the warm birth group (n = 10) and cold birth group (n = 13). Right, the warm fertilization group (n = 6) and cold fertilization group (n = 17). (c) Nutrient composition of the test meal. Participants ingested the nutritionally balanced food and liquid containing 500 kcal/63 kg body weight (BW). (d) Correlation between FFM and resting EE at thermoneutral 27°C. (e) Postprandial whole-body EE adjusted for FFM in the warm birth (n = 10) and cold birth (n = 13) groups. (f) Postprandial whole-body EE adjusted for FFM in the warm fertilization (n = 6) and cold fertilization (n = 17) groups. (a, b, d-f) Biologically independent samples. (a, b, e, f) Data are mean ± s.e.m.; two-tailed P values by unpaired Student's t-test (a, b) or two-way repeated measures ANOVA (e, f). (d) Pearson's correlation coefficient (r) and two-tailed P value. Source data (a) Participant profile, physical activity, and TEE of the warm birth (n = 22) and cold birth groups (n = 19) and the warm fertilization (n = 20) and cold fertilization groups (n = 21) in Cohort 5. (b) Correlations of daily TEE measured by the DLW method with age and anthropometric parameters. (c) Multivariate regression analysis for predicting daily TEE (n = 41, model 1, R2 = 0.794, P < 0.001). The TEE as dependent variable. Age, height, weight, FFM, fat mass, step count, physical activity level as independent variables. (d) Normalized daily TEE. Residual EE in multivariate regression model 1 in c was calculated for each subject as body size- and physical activity-independent TEE. Warm birth (n = 22); cold birth (n = 19); warm fertilization (n = 20); cold fertilization (n = 21). (e) A disaggregated analysis of TEE adjusted for FFM and step count for sex. Left: male, n = 19. Right: female, n = 22. (a-e) Biologically independent samples. (a, d, e) Data are mean ± s.e.m.; two- (a, d) or one-tailed (e) P values by unpaired Student's t-test. Percentage of sex: one-tailed P values by Fisher's exact test. (b) Pearson's correlation coefficient (r) and two-tailed P values. (c) Unstandardized β with 95% CIs as error bars, standardized β, and two-tailed P values by multivariate regression analysis with backward stepwise method (model 1). Source data (a) Correlations between BAT activity by FDG-PET/CT and adiposity-related parameters including BMI, body fat content, body fat mass, FFM, abdominal total, subcutaneous, and visceral fat areas, and waist circumference in healthy male participants (Cohort 1). (b) Correlations between BAT-d by NIR-TRS and adiposity-related parameters including BMI, body fat content, skeletal muscle mass, visceral fat area, waist circumference, SBP, DBP, and heart rate in participants with wide range of age (Cohort 2). (a, b) Biologically independent samples. Pearson's correlation coefficient (r) and two-tailed P value by correlation analysis. Numbers of participants (n) are indicated on the panels. Source data (a) Impacts of the seasons of birth and fertilization on abdominal total, subcutaneous, and visceral fat areas and waist circumference in Cohort 1. (b) Impacts of the seasons of birth and fertilization on skeletal muscle mass in Cohort 2. (c) Impacts of the seasons of birth and fertilization on SBP, DBP and heart rate in Cohort 2. (a-c) Biologically independent samples. Data are mean ± s.e.m.; two-tailed P value by unpaired Student's t-test. Numbers of participants (n) are indicated on the graph. Source data Climatological annual cycle of meteorological parameters in Tokyo, Japan. Daily maximum (max.) and minimum (min.) outdoor temperatures (temp.), precipitation, humidity, sunshine duration, atmospheric pressure, and diurnal range of outdoor temperature for 11 years (2010–2020) were obtained from the climate databases constructed by the JMA and NARO. Sunrise time and sunset time for 7 years (2012–2020) were obtained from the database constructed by the NAOJ to calculate daytime length. Diurnal temperature fluctuation was calculated as differences between maximum and minimum temperature and between maximum and mean temperature. For all meteorological parameters, 11-day moving average was calculated for each calendar day. Data are mean ± s.e.m., n = 11 except daytime length (n = 9). Source data (a) Multivariate logistic regression analysis for predicting independent effect of diurnal temperature gap, calculated as difference between maximum and mean outdoor temperature, on BAT activity (n = 93, model 3). The calculated diurnal temperature gap was added in the model in addition to daily mean temperature and the other meteorological parameters. Age, BMI, the medical history of low birth weight, and lifestyle factors such as smoking and shift work status were included in the model as potential confounding factors. (b) Association between BAT prevalence and diurnal temperature gap in a. The participants were divided into three groups according to the tertile of diurnal temperature gap in the five pregnancy periods. The number of participants of high and low BAT subjects were indicated on the graph. (a, b) Biologically independent participants. (a) Data are presented as adjusted ORs with 95% CIs as error bars and two-tailed P values by multivariate logistic regression analysis with backward stepwise method. High and low BAT coded as 1 and 0, respectively, as the dependent variable. The models were adjusted for the tertile values for age and BMI, the medical history of low birth weight, smoking status, shift work status. (b) Data are percentage with two-tailed P values by Chi-squared linear-by-linear association test. Source data Supplementary Fig. 1, and Study Protocol. Supplementary Table 1 Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Statistical source data. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Reprints and permissions Yoneshiro, T., Matsushita, M., Fuse-Hamaoka, S. et al. Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01249-2 Download citation Received: 08 August 2024 Accepted: 18 February 2025 Published: 07 April 2025 DOI: https://doi.org/10.1038/s42255-025-01249-2 Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative Advertisement Nature Metabolism (Nat Metab) ISSN 2522-5812 (online) © 2025 Springer Nature Limited Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

There's Now a Third Way to Inherit Traits That Isn't Your DNA or RNA, Scientists Say

Source: {'href': 'https://www.popularmechanics.com', 'title': 'Popular Mechanics'} Published: 2025-04-07 13:00:00

And they discovered it completely by accident. Gear-obsessed editors choose every product we review. We may earn commission if you buy from a link. Why Trust Us? Containing some 3.2 billion base pairs, the human genome is far from a simple set of genetic instructions, but the process of inherited traits from parent to child is often described as a straightforward one. The genes of one parent combine with the genes of another, which forms the genetic traits of their offspring. While DNA and RNA are the primary pathways through which traits are inherited, a new study from the University of Toronto suggests its not the only pathway—and they came across this groundbreaking discovery by complete accident. Brent Derry's lab at the University of Toronto led by Matthew Eroglu—now a postdoctoral research scientist at Columbia University—first began studying cancer signaling pathways using the hermaphroditic worm Caenorhabditis elegans. Surprisingly, over the course of the study the researchers noticed that the worms—which could be both male and female—became increasingly less fertile and more feminine over subsequent generations until eventually reaching complete sterilization. Intrigued by this epigenetic trait—changes that affect genes without altering the DNA sequence itself—Eroglu and his team kept digging and discovered the culprit: amyloids. The results were published in the journal Nature Cell Biology. "There are a lot of traits and disorders that we know are passed on from parents to offspring if we look at family trees and so on,” Eroglu said in a press statement, “but when people have done genome-wide association studies trying to link these traits to mutations or variants in genes, they frequently fall short of explaining all of the heritability that we see.” One of the reasons could be epigenetic impacts such as these amyloids. Amyloids are extracellular proteins that, when built up in the body, can cause neurological diseases like Alzheimer's (though the amyloids in this study aren't exactly the same). When examining the increasingly feminizing worms, the authors noted that they contained “autofluorescent green dots,” as the website El País describes. They called these dots “herasomes,” and inside them were amyloid-like structures that are known to have the DNA-like ability to replicate themselves, making them possible inheritance vectors. The researchers then performed a variety of tests, subjecting some worms to heat-induced stress while deactivating certain genes to test their hypothesis. These experiments only confirmed that amyloid structures in the herasomes are the cause behind this hyper-feminine (and eventual sterilization) phenomenon. Of course hermaphroditic worms are one thing, and humans traits are another, so future studies will need to investigate if similar pathways are possible in humans (though the authors suggest they don't see why they wouldn't). “There's this alternate inheritance mechanism on top of DNA,” Eroglu said in a press statement. “Could we discover something that, in fact, doesn't change sex but changes some other traits? Or predict diseases that we couldn't base on DNA alone?” Darren lives in Portland, has a cat, and writes/edits about sci-fi and how our world works. You can find his previous stuff at Gizmodo and Paste if you look hard enough. We Totally Missed a Big Part of Our Immune System Scientists Took A Huge Step Towards Curing Anthrax Scientists Want to Grow Spare Human Bodies. This Is the Secret to Being a Supercentenarian Man Survives With Titanium Heart for 100 Days Humans May Be Able to Grow New Teeth in 6 Years New Medicine May Help New Teeth Grow Inside the Chernobyl Dogs' Strange Genetic Changes This is How Magic Mushrooms Warp Our Reality Breathing Like This Can Alter Your Consciousness Scientists Found the Speed Limit of Human Thought Unraveling the Burden of Kidney Dialysis A Part of Hearst Digital Media We may earn commission from links on this page, but we only recommend products we back. ©2025 Hearst Magazine Media, Inc. All Rights Reserved.

Asteroid 2024 YR4 Could Hit the Moon, Measles Cases Rise, and States Sue HHS

Source: {'href': 'https://www.scientificamerican.com', 'title': 'Scientific American'} Published: 2025-04-07 10:00:00

April 6, 2025 American Lifespans, Monkeys That Yodel, Measles, and More States sue HHS for public health cuts, measles cases continue to rise, and a study finds Americans live shorter lives compared with their European counterparts. By Rachel Feltman, Fonda Mwangi & Alex Sugiura Anaissa Ruiz Tejada/Scientific American Rachel Feltman: Happy Monday, listeners! And happy April. For Scientific American's Science Quickly, I'm Rachel Feltman. Let's kick off the week with a quick roundup of science news you might have missed. To start we have some public health updates. Last Friday the Texas health department reported that there have been 481 known measles cases since late January, up from 400 on March 28. Texas Public Radio recently reported that several children with measles have also needed treatment for toxic levels of vitamin A. As I explained in the March 10 news roundup episode, U.S. Health and Human Services Secretary Robert F. Kennedy Jr. has publicly touted vitamin A supplementation for measles patients while seemingly downplaying the importance of vaccines. According to a recent report by ProPublica, U.S. Centers for Disease Control and Prevention leaders blocked the release of an assessment on the ongoing outbreak written by the agency's own experts. The planned messaging around the assessment reportedly would have emphasized the need for vaccinations to prevent measles. In a statement to ProPublica, a CDC spokesperson claimed that this report was not published “because it does not say anything that the public doesn't already know” and that the CDC still presents vaccines as “the best way to protect against measles.” But the spokesperson went on to add that “the decision to vaccinate is a personal one,” saying folks “should be informed about the potential risks and benefits associated with vaccines.” Now the good news is that we know a lot about the risks associated with the measles vaccine, and they're extremely low. For instance, one study used the mass vaccination of 14.3 million kids in China from September 2007 to March 2008 to track the rate of serious adverse events. The researchers saw a rate of just over two such events for every million vaccine doses given. In contrast, one in every 1,000 cases of measles is associated with encephalitis, or swelling of the brain, which can be deadly. And several major studies have found no link between the measles-mumps-rubella vaccine and autism diagnoses. If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today. The CDC's stifling of this new measles report isn't the only indication that the current administration is downplaying the importance of vaccines. Late last month top U.S. Food and Drug Administration vaccine official Peter Marks resigned from his position. According to the Wall Street Journal and New York Times, Marks was given the choice between quitting and being fired. Meanwhile, lawmakers from 23 states and Washington, D.C., are suing HHS for slashing more than $11 billion in funding for public health initiatives. We actually mentioned those cuts in last week's news roundup. They mainly target funds that were allocated to local and state health departments during the peak of the COVID pandemic. According to the lawsuit, which was filed last Tuesday, that money was never earmarked as being solely for pandemic-response initiatives like COVID testing. Some of the funding has been directed toward strengthening public health infrastructure to make states and communities more resilient to pandemics and other major crises, including measles outbreaks, the spread of bird flu and the ongoing opioid epidemic, according to the lawmakers. Last week, NBC News reported that the Dallas County Health and Human Services Department had to cancel dozens of planned free measles vaccination clinics due to these same funding cuts. Speaking of health in the U.S., a new study suggests that folks in America live shorter lives than their economic counterparts in Europe. In a study published last Wednesday in the New England Journal of Medicine, researchers compared data from more than 73,000 adults aged 50 to 85. The scientists found, unsurprisingly, that in any given country, people with more money tended to live longer. But the researchers also found that the wealthiest U.S. subjects had shorter lifespans, on average, than the richest participants from Europe. And in parts of western Europe such as Germany, France and the Netherlands some of the poorest residents had lifespans in line with the wealthiest Americans. The study authors say this is a reminder that systemic issues in the U.S. such as stress, diet and environmental contaminants aren't something you can spend your way out of. Okay, let's pivot to lighter news. Remember that killer asteroid we were all worried about for a minute? Wouldn't you rather talk about killer asteroids? I know I would. The good news is that observations made with the James Webb Space Telescope have confirmed that 2024 YR4 functionally has zero chance of hitting Earth in 2032. Yay! The bad news is that there's still a nonzero possibility that our moon will take the hit instead—about a 2 percent chance, to be exact. And it turns out that a moon collision might not be bad news at all. Several astronomers told New Scientist that such an event would represent a huge opportunity for research. One even said he had his fingers crossed. We know the moon is pelted with smaller asteroids all the time, and its iconically pocked surface tells us it's taken on bigger bruisers in the past. Knowing in advance that something was going to collide with the moon—and having the time to be certain of its dimensions and trajectory—would enable unprecedented study of the formation of lunar craters. That could help us understand the moon's past. We'll wrap up with a fun animal story. Because you've earned it! When you think of yodeling you probably imagine people in the Alps wearing wooden shoes or maybe Julie Andrews in The Sound of Music. But a study published last Thursday throws a dark horse into the competition for world's best yodeler: monkeys. Researchers were interested in structures called vocal membranes, which apes and monkeys have in their throats but humans no longer do. Using CT scans of several species of monkey, along with computer simulations and fieldwork, researchers found that these structures help monkeys accomplish so-called voice breaks, where they quickly switch between using their vocal membranes and vocal folds to produce sound. The result is that quick change in frequency we hear when humans yodel or make that quintessential Tarzan yelp. Here's an example from the tufted capuchin. [CLIP: A tufted capuchin vocalizes.] Feltman: That might not sound very yodel-y, but things get clearer when you slow the call down. [CLIP: The tufted capuchin's vocalization is slowed down.] Feltman: Previous research has suggested that humans gave up these membranes to make our speech more stable. But I guess that might have come at the cost of some sick yodelling skills. That's all for this week's science news roundup. We'll be back on Wednesday. Science Quickly is produced by me, Rachel Feltman, along with Fonda Mwangi, Kelso Harper, Naeem Amarsy and Jeff DelViscio. This episode was edited by Alex Sugiura. Shayna Posses and Aaron Shattuck fact-check our show. Our theme music was composed by Dominic Smith. Subscribe to Scientific American for more up-to-date and in-depth science news. For Scientific American, this is Rachel Feltman. Have a great week! Rachel Feltman is former executive editor of Popular Science and forever host of the podcast The Weirdest Thing I Learned This Week. She previously founded the blog Speaking of Science for the Washington Post. Fonda Mwangi is a multimedia editor at Scientific American. She previously worked as an audio producer at Axios, The Recount and WTOP News. She holds a master's degree in journalism and public affairs from American University in Washington, D.C. Alex Sugiura is a Peabody and Pulitzer Prize–winning composer, editor and podcast producer based in Brooklyn, N.Y. He has worked on projects for Bloomberg, Axios, Crooked Media and Spotify, among others. Learn and share the most exciting discoveries, innovations and ideas shaping our world today. Follow Us: Scientific American is part of Springer Nature, which owns or has commercial relations with thousands of scientific publications (many of them can be found at www.springernature.com/us). Scientific American maintains a strict policy of editorial independence in reporting developments in science to our readers. © 2024 SCIENTIFIC AMERICAN, A DIVISION OF SPRINGER NATURE AMERICA, INC.ALL RIGHTS RESERVED.

Breakthrough Prizes Awarded to Obesity-Drug Pioneers and Large Hadron Collider Physicists

Source: {'href': 'https://www.scientificamerican.com', 'title': 'Scientific American'} Published: 2025-04-07 04:01:00

April 7, 2025 4 min read Obesity-Drug Pioneers and Large Hadron Collider Physicists win $3-Million Breakthrough Prizes Advances recognized by science's most lucrative awards include high-energy physics experiments and groundbreaking weight-loss treatments By Zeeya Merali & Nature magazine The Breakthrough prize trophy's design is inspired by imagery from science, including black holes, seashells and the structure of DNA. Breakthrough Prize Five scientists who contributed to the development of the blockbuster weight-loss drugs Ozempic and Wegovy have picked up one of this year's US$3-million Breakthrough prizes — the most lucrative awards in science. Originally developed to treat diabetes, these drugs work by mimicking a hormone called glucagon-like peptide 1 (GLP-1) that controls blood sugar levels and helps to curb appetite. “This class of drugs truly saves lives, changes lives and brings joy back to people's lives,” says Ziyad Al-Aly, a physician-scientist at the Veterans Affairs St. Louis Health Care System in Missouri, who recently led a massive study analysing data from almost two million people to evaluate the effects of such medication. This life-sciences prize is shared between the four researchers who discovered and characterized GLP-1 – endocrinologist Daniel Drucker at the University of Toronto, Canada; physician-researchers Joel Habener at Harvard Medical School in Boston, Massachusetts and Jens Juul Holst at the University of Copenhagen; and chemist Svetlana Mojsov at The Rockefeller University in New York City — along with Lotte Bjerre Knudsen of pharmaceutical company Novo Nordisk in Bagsværd, Denmark, who spearheaded the development of drugs based on these discoveries. If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today. In the 1990s, Drucker and his colleagues realized that GLP-1 caused animals to eat less and lose weight. Knudsen stablized the drug by adding fatty-acid chains, enabling it to bind to proteins in the blood, which prevents it from breaking down rapidly once injected. “It's a tremendous honour to receive this prestigious award,” says Drucker. “But the most amazing gratification is when someone comes to my office and says, ‘I lost 40 pounds [18 kg] and I feel healthy'.” The award is one of six Breakthrough prizes to be awarded this year in life sciences, physics and mathematics. Unusually for a major award, one of the fundamental-physics prizes was awarded to a grand total of 13,508 physicists spanning four collaborations at CERN, Europe's particle physics laboratory near Geneva in Switzerland. Through experiments using the Large Hadron Collider (LHC), these researchers have taken multiple precision measurements over the past decade to probe, and so far confirm, the standard model of particle physics. “We're honoured the award was made to the entire collaboration because without all those people we could not have made these advances,” says Patricia McBride, a spokesperson for CERN's CMS collaboration. The prize money will be used to fund international students to visit CERN, she adds. The award is well deserved, says Brian Rebel, a particle physicist at the University of Wisconsin–Madison. “Finding the Higgs [boson] in 2012 was a once-in-lifetime event, but it was only the first step,” Rebel says. Since then, LHC scientists have been pinning down the mass of the Higgs and its interactions, as well as discovering 72 new particles, investigating antimatter and probing the nature of the ‘quark–gluon plasma' that existed soon after the Big Bang. “It takes a small army to create the tools to test and validate these results,” says Rebel. Another Breakthrough prize in fundamental physics was awarded to one of the architects of the standard model, theoretical physicist Gerard 't Hooft at Utrecht University in the Netherlands, who also won a share of the 1999 Nobel prize in physics for his work on the weak nuclear force, and contributed to understanding the strong nuclear force. “A beautiful synthesis emerges when one's mathematics is linked to particles actually seen in the world,” says 't Hooft, adding that he is “honoured” to win the prize. The mathematics prize went to Dennis Gaitsgory at the Max Planck Institute of Mathematics in Bonn, Germany, for numerous contributions to the development of the Langlands programme — dubbed the ‘grand unified theory of mathematics' because it brings together the disciplines of number theory, geometry and function fields. And two other prizes in the life sciences were awarded — one shared between neuroscientist Stephen Hauser at the University of California, San Francisco, and epidemiologist Alberto Ascherio at Harvard University, for research on the drivers of multiple sclerosis (MS), a disease caused by damage to myelin, the material that surrounds and insulates nerve fibres. In the 1990s, Hauser and colleagues demonstrated that antibodies produced by the immune system's B cells were likely to be behind the damage4. This initially invited scepticism because it had been assumed that T cells were the culprits, and Hauser recalls being “devastated” at being refused funding because his ideas were deemed “biologically implausible”. “The Breakthrough Prize is recognition of the importance of ‘stick-to-it-ness',” says Hauser. Independently, in 2022, Ascherio and his colleagues definitively established that infection with the Epstein–Barr virus drastically heightens a person's risk of developing MS. The final life-sciences prize went to David Liu, a molecular biologist at the Broad Institute in Cambridge, Massachusetts, for developing technologies that use CRISPR gene-editing to rewrite segments of DNA. His techniques are being employed in clinical trials for the treatment of T-cell leukaemia, sickle-cell disease, β-thalassemia and high cholesterol. The Breakthrough prizes were founded in 2012 and are sponsored by Yuri Milner, a Russian–Israeli billionaire, and other Internet entrepreneurs, including Meta's chief executive Mark Zuckerberg. This article is reproduced with permission and was first published on April 5, 2025. Zeeya Merali is a freelance writer based in London and author of A Big Bang in a Little Room (Basic Books, 2017). First published in 1869, Nature is the world's leading multidisciplinary science journal. Nature publishes the finest peer-reviewed research that drives ground-breaking discovery, and is read by thought-leaders and decision-makers around the world. Learn and share the most exciting discoveries, innovations and ideas shaping our world today. Follow Us: Scientific American is part of Springer Nature, which owns or has commercial relations with thousands of scientific publications (many of them can be found at www.springernature.com/us). 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