Scientists at UC San Francisco have now pinpointed a protein that appears to drive much of this decline.

FTL1 Emerges as a Key Driver of Brain Aging

To understand what changes with age, the researchers tracked shifts in genes and proteins in the hippocampus of mice over time. Among everything they examined, only one stood out as consistently different between young and old animals. That protein is called FTL1.

Older mice showed higher levels of FTL1. At the same time, they had fewer connections between neurons in the hippocampus and performed worse on cognitive tests.

How FTL1 Alters Brain Function

When the team boosted FTL1 levels in young mice, the effects were striking. Their brains began to look and function more like those of older mice, and their behavior reflected this shift.

Lab experiments revealed more detail. Nerve cells engineered to produce high amounts of FTL1 developed simplified structures, forming short, single extensions instead of the complex, branching networks seen in healthy cells.

Reversing Memory Decline by Lowering FTL1

The most surprising result came when researchers reduced FTL1 in older mice. The animals showed clear signs of recovery. Connections between brain cells increased, and their performance on memory tests improved.

“It is truly a reversal of impairments,” said Saul Villeda, PhD, associate director of the UCSF Bakar Aging Research Institute and senior author of the paper, which was published in Nature Aging. “It’s much more than merely delaying or preventing symptoms.”

Metabolism Link Points to New Treatments

Further experiments showed that FTL1 also affects how brain cells use energy. In older mice, higher levels of the protein slowed cellular metabolism in the hippocampus. However, when researchers treated these cells with a compound that boosts metabolism, the negative effects were prevented.

Hope for Future Brain Aging Therapies

Villeda believes these findings could pave the way for treatments that target FTL1 and counter its effects in the brain.

“We’re seeing more opportunities to alleviate the worst consequences of old age,” he said. “It’s a hopeful time to be working on the biology of aging.”

Authors and Funding

Other UCSF authors are Laura Remesal, PhD, Juliana Sucharov-Costa, Karishma J.B. Pratt, PhD, Gregor Bieri, PhD, Amber Philp, PhD, Mason Phan, Turan Aghayev, MD, PhD, Charles W. White III, PhD, Elizabeth G. Wheatley, PhD, Brandon R. Desousa, Isha H. Jian, Jason C. Maynard, PhD, and Alma L. Burlingame, PhD. For all authors see the paper.

This work was funded in part by the Simons Foundation, Bakar Family Foundation, National Science Foundation, Hillblom Foundation, Bakar Aging Research Institute, Marc and Lynne Benioff, and the National Institutes of Health (AG081038, AG067740, AG062357, P30 DK063720). For all funding see the paper.

Manipulating light at extremely small scales is key to advancing modern technology. As traditional electronics begin to reach their limits, photonics offers an alternative by using light instead of electrons to carry information. Because photons move faster and do not have mass like electrons, devices based on light could become both quicker and smaller, opening the door to more powerful and compact technologies.

The Challenge of Light’s Wavelength

Light behaves both as a particle and as a wave, and this wave nature introduces a limitation. Each type of light has a wavelength, which determines how small a structure can be while still controlling it effectively. Visible light has wavelengths of several hundred nanometers, while infrared light extends to a micrometer or more. This raises an important question: can light be confined in structures smaller than its own wavelength?

The research team demonstrated that this is indeed possible. By engineering a subwavelength grating, they were able to trap infrared light within a layer only 40 nanometers thick. This structure consists of closely spaced parallel strips that interact with light similarly to a prism. When these strips are positioned closer together than the wavelength of light, the grating can act like a near-perfect mirror while also holding the light inside a very small volume.

Why Molybdenum Diselenide Works So Well

Earlier versions of such gratings, made from materials like silicon or gallium compounds, required thicknesses of several hundred nanometers to function effectively. Reducing their size caused them to lose their ability to confine light. The key difference in this new approach is the use of molybdenum diselenide, which has a much higher refractive index. In simple terms, light slows down more inside this material than in others. While light slows by about 1.5 times in glass and roughly 3.5 times in silicon or gallium arsenide, it slows by about 4.5 times in MoSe₂. This strong slowing effect allows the structure to shrink dramatically while still trapping light efficiently, resulting in a layer more than a thousand times thinner than a human hair.

Turning Infrared Light Into Blue Light

MoSe₂ also brings additional advantages. Like graphene, it forms layered structures, but unlike graphene, it is a semiconductor. It also exhibits nonlinear optical behavior, including a process known as third harmonic generation. In this process, three infrared photons combine into one photon with a higher frequency, effectively converting infrared light into visible blue light. Because the grating strongly concentrates infrared light, this conversion becomes much more efficient. The researchers found that the effect is more than 1,500 times stronger compared to a flat layer of the same material.

Another major advance lies in how the material was produced. Previously, thin layers of MoSe₂ were created using exfoliation — a method similar to peeling layers off a crystal with adhesive tape. While simple, this technique is inconsistent and limited to very small areas, typically around ten square micrometers, which is not suitable for real-world devices.

To overcome this, the team used molecular beam epitaxy (MBE), a well-established method for growing semiconductor layers. This approach allowed them to produce large, uniform MoSe₂ films spanning several square inches. Despite this large size, the layer maintained a thickness of just 40 nanometers, giving it an extreme aspect ratio. For comparison, the thickness-to-size ratio of this layer is about one to a million, while a typical A4 sheet of paper has a ratio closer to 1:2000.

Toward Practical Photonic Applications

These results suggest that molybdenum diselenide produced in this way could significantly change how light is controlled in future technologies. Structures no longer need to be thick to manipulate light effectively. Instead, extremely thin layers can perform the same function, and in some cases even better. Because the production method is scalable, the path toward real-world applications, such as photonic integrated circuits, is becoming increasingly realistic.

Funding and Support

The research was funded by the National Science Centre under projects OPUS 2020/39/B/ST7/03502 and 2021/41/B/ST3/04183, with European Union funds under ERC-ADVANCED grant No. 101053716, the Foundation for Polish Science under project ENG.02.01-IP.05-T004/23, and by the University of Warsaw under the Excellence Initiative – Research University (IDUB) New Ideas in Priority Research Areas II No. 501-D111-20-2004310 titled “Ultrathin subwavelength gratings based on dichalcogenides.”

The team examined a region of Alaska’s North Slope roughly the size of Wisconsin, where hundreds of rivers and streams drain into the Beaufort Sea. Using 44 years of model data at a resolution of one kilometer, they found that runoff is rising sharply, rivers are carrying increasing amounts of carbon, and the thaw season is extending later into the year, now reaching late summer and fall. The findings were published in Global Biogeochemical Cycles.

Arctic Rivers Play an Outsized Role in the Global System

Rivers in the Arctic have a surprisingly large influence on the planet. They deliver about 11% of the world’s river water into an ocean that holds just 1% of global ocean volume. This makes the Arctic Ocean especially sensitive to changes occurring in rivers and streams across the region.

Although melting snow supplies much of this water, thawing permafrost is becoming increasingly important. The ground contains a layer known as the “active layer,” which freezes and thaws each year. As the climate warms, this layer is getting deeper, allowing more groundwater to flow into Arctic rivers.

Thawing Soil Is Releasing Ancient Carbon

The active layer holds large quantities of organic material that have been frozen for thousands of years. As it deepens, more of this material is released into rivers as dissolved organic carbon (DOC), eventually reaching the ocean.

The Arctic Ocean already receives a disproportionate share of this carbon compared to other parts of the world. Each year, more than 275 million tons of it are converted into carbon dioxide, adding to global warming and creating a feedback loop that can intensify climate change.

Limited Observations Make Modeling Essential

Understanding how individual rivers respond to warming is challenging because direct measurements in northern Alaska are limited.

“What makes this question so hard to answer is that direct observations are very sparse in northern Alaska,” says Rawlins, extension associate professor of Earth, Geographic, and Climate Sciences at UMass Amherst. “There are nowhere near enough river sample measurements to quantify inputs to estuaries along the entire Alaskan North Slope.”

To address this gap, Rawlins developed the Permafrost Water Balance Model over the past 25 years. This model estimates key processes such as snow accumulation, melt, and changes in the active layer to better represent real conditions. In 2021, it was expanded to simulate dissolved organic carbon, and in 2024 it was applied across 22.45 million square kilometers of Arctic land.

The model suggests that over the next 80 years, the Arctic could experience up to 25% more runoff, 30% more subsurface flow, and increasing dryness in southern areas.

High-Resolution Modeling Reveals New Patterns

Previous versions of the model used grid cells that were 25 kilometers wide. This study improves on that by capturing changes at a much finer scale.

“We’ve typically run the model on 25-kilometer grid cells,” says Rawlins. “This new study is the first time anyone has captured such a wide area of the Arctic — about the size of Wisconsin — down to the kilometer scale, and over such a long period of time: our model simulates daily river flows and coastal exports over 44 years from 1980 to 2023.”

Running the model required substantial computing power. Each simulation took 10 continuous days on a supercomputer at the Massachusetts Green High Performance Computing Center.

“Our freshwater and DOC inputs to coastal estuaries will be useful to a broad range of stakeholders interested in these unique ecosystems in coastal northern Alaska,” says Rawlins, “including the Beaufort Lagoon Ecosystems project, which is helping to quantify exactly what’s coming through these coastal estuaries.”

Northwest Alaska Shows the Biggest Carbon Increases

The researchers found that while runoff and thawing are increasing across the region, the largest rise in carbon export is occurring in northwest Alaska.

“It’s flatter over there,” says Rawlins, “which means there’s much more carbon from decaying matter in the permafrost that has been accumulating for tens of thousands of years. This is ancient carbon. The further east you go, the more mountainous it becomes. The soil is rockier and sandier, and so far less DOC is mobilized as the permafrost thaws.”

A Longer Thaw Season Is Driving Change

One of the most notable findings is how much of the change is tied directly to permafrost thaw. The thaw season now lasts longer than in the past, extending into September and even October.

These changes are likely affecting salinity, nutrient cycles, and food webs in the Beaufort Sea. Researchers are now studying how ice wedge polygons, a common Arctic landscape feature, influence how water and carbon move toward coastal areas.

A Critical Gap in Understanding the Carbon Cycle

“How much DOC finds its way to the ocean via rivers and streams is a part of the carbon cycle we don’t know much about,” says Rawlins. “We desperately need more of these land-to-ocean connection studies if we’re to fully grapple with the problem of global warming and the effects it will have on coastal ecosystems.”

The research was supported by the U.S. National Science Foundation and NASA.

New research suggests otherwise, according to a Keck Medicine of USC study published today in Clinical Gastroenterology and Hepatology. 

Researchers discovered that people with metabolic dysfunction–associated steatotic liver disease (MASLD), the most common liver condition in the country affecting one-in-three adults, face significantly higher risk of liver fibrosis, or harmful scarring of the liver, if they engage in episodic heavy drinking. Episodic heavy drinking is four or more drinks in one day for women and five or more drinks in one day for men, at least once a month. 

Those who consume large amounts of alcohol in a single day at least once per month are three times more likely to develop advanced liver fibrosis than individuals who spread out the same total alcohol intake over time, according to the findings. 

Younger adults and men were more likely to report episodic heavy drinking, and the more drinks consumed at one time, the more liver fibrosis people tended to have. 

“This study is a huge wake-up call because traditionally, physicians have tended to look at the total amount of alcohol consumed, not how it is consumed, when determining the risk to the liver,” said Brian P. Lee, MD, MAS, a hepatologist and liver transplant specialist with Keck Medicine and principal investigator of the study. “Our research suggests that the public needs to be much more aware of the danger of occasional heavy drinking and should avoid it even if they drink moderately the rest of the time.”  

How the study was conducted 

Lee and his colleagues used data from the nationally representative National Health and Nutrition Examination Survey, a long-running health survey of the United States population. They included data from more than 8,000 adults, collected between 2017 and 2023. In particular, they looked at the link between episodic heavy drinking and advanced liver fibrosis to understand how drinking patterns — not just total drinks — may cause harm even to moderate drinkers, which is considered seven drinks a week for women and 14 or less for men.  

The research team focused on MASLD because of its prevalence among Americans. MASLD affects people with excess weight, obesity or other metabolic conditions, such as Type 2 diabetes, high blood pressure or high cholesterol, and is on the rise. Additionally, while MASLD is not defined as alcohol-related, Lee and his colleagues wanted to explore if alcohol did in fact play some role in the condition. 

More than one-half of the adults included in the study reported episodic heavy drinking and almost 16% of patients with MASLD were episodic heavy drinkers. 

The researchers compared people with MASLD with the same age, sex and average weekly alcohol consumption, segmenting some as episodic heavy drinkers and others as non-episodic heavy drinkers, to reach their conclusion that episodic heavy drinkers with MASLD had nearly three times higher odds of experiencing advanced liver fibrosis.  

Lee speculates that episodic heavy drinking can harm the liver both directly and indirectly. Drinking large amounts of alcohol at once can overwhelm the liver and increase inflammation, which leads to scarring and damage. People with MASLD may be particularly at risk, as Lee’s previous research has shown that obesity, high blood pressure and other conditions associated with MASLD can more than double liver disease risk. 

Alcohol-related liver disease has more than doubled in the last two decades, according to Lee. He believes this trend is driven by pandemic-era surges in drinking and an increase in people with risk factors for MASLD, like obesity and diabetes.  

“Although this study focused on patients with MASLD, these findings may also be pertinent to a broader patient population,” said Lee. “With more than half of adults reporting some episodic heavy drinking, this issue deserves further attention from both physicians and researchers to help better understand, prevent and treat liver disease.” 

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For more information about Keck Medicine of USC, please visit news.KeckMedicine.org. 

The study was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism, grant number K23AA029752. 

High blood pressure (hypertension) affects about 1.3 billion people worldwide. In nearly half of these cases, the condition is either uncontrolled or does not respond well to treatment. This greatly increases the risk of heart attack, stroke, kidney disease, and early death. In the UK alone, around 14 million people are living with hypertension.

Large International Trial of Baxdrostat

The international BaxHTN trial, led by Professor Bryan Williams (UCL Institute of Cardiovascular Science) and funded by AstraZeneca, tested a new drug called baxdrostat, which is taken as a tablet. The study included nearly 800 patients across 214 clinics around the world.

The research was supported by the NIHR Biomedical Research Centre at UCLH.

The results were presented at the European Society of Cardiology (ESC) Congress 2025 in Madrid and were also published in the New England Journal of Medicine.

Significant Blood Pressure Reductions

After 12 weeks, patients taking baxdrostat (1 mg or 2 mg once daily in pill form) experienced an average drop in blood pressure of about 9 to 10 mmHg more than those taking a placebo. This level of reduction is considered large enough to lower the risk of cardiovascular events.

Around 40 percent of patients taking baxdrostat reached healthy blood pressure levels, compared with fewer than 20 percent in the placebo group.

Principal Investigator, Professor Williams, who is presenting the results at ESC, said: “Achieving a nearly 10 mmHg reduction in systolic blood pressure with baxdrostat in the BaxHTN Phase III trial is exciting, as this level of reduction is linked to substantially lower risk of heart attack, stroke, heart failure and kidney disease.”

How Baxdrostat Targets a Key Hormone

Blood pressure is heavily influenced by a hormone called aldosterone, which helps regulate salt and water levels in the body.

In some individuals, the body produces too much aldosterone. This leads to excess salt and water retention, raising blood pressure and making it difficult to control.

Scientists have long tried to address this imbalance, but it has proven challenging.

Baxdrostat works by blocking the production of aldosterone, directly targeting a major cause of high blood pressure (hypertension).

A New Approach to Difficult Cases

Professor Williams, Chair of Medicine at UCL, said: “These findings are an important advance in treatment and in our understanding of the cause of difficult to control blood pressure.

“Around half of people treated for hypertension do not have it controlled, however this is a conservative estimate and the number is likely higher, especially as the target blood pressure we try to reach is now much lower than it was previously.^[1]

“In patients with uncontrolled or resistant hypertension, the addition of baxdrostat 1mg or 2mg once daily to background antihypertensive therapy led to clinically meaningful reductions in systolic blood pressure, which persisted up to 32 weeks with no unanticipated safety findings.

“This suggests that aldosterone is playing an important role in causing difficult to control blood pressure in millions of patients and offers hope for more effective treatment in the future.”

Rising Global Burden and Future Potential

In the past, higher rates of hypertension were mainly seen in wealthier Western countries. However, changing diets, including reduced salt intake in some regions, have shifted the global burden. Today, far more cases are found in Eastern and lower income countries. More than half of all people with hypertension live in Asia, including 226 million in China and 199 million in India.^[2]

Professor Williams added: “The results suggest that this drug could potentially help up to half a billion people globally — and as many as 10 million people in the UK alone, especially at the new target level for optimal blood pressure control.”

Notes

1. The ESC 2024 hypertension guidelines recommended a target blood pressure of less than 130/80 mmHg. Prior to 2024 the target had been 140/90 mmHg.
2. Figures from Blood Pressure UK

“Claws are never in that location in a Cambrian arthropod,” said Lerosey-Aubril, “It took me a few minutes to realize the obvious, I had just exposed the oldest chelicera ever found.”

Oldest Known Chelicerate Identified

In a study published in Nature, Research Scientist Rudy Lerosey-Aubril and Associate Professor Javier Ortega-Hernández, Curator of Invertebrate Paleontology in the Museum of Comparative Zoology – both in the Department of Organismic and Evolutionary Biology at Harvard – describe Megachelicerax cousteaui, a 500 million year old marine predator discovered in Utah’s West Desert. It is now recognized as the earliest known chelicerate, a group that includes spiders, scorpions, horseshoe crabs, and sea spiders. This finding extends the known history of chelicerates by about 20 million years.

“This fossil documents the Cambrian origin of chelicerates,” noted Lerosey-Aubril, “and shows that the anatomical blueprint of spiders and horseshoe crabs was already emerging 500 million years ago.”

Detailed Anatomy of an Ancient Predator

Revealing the fossil’s structure required patience and precision. Lerosey-Aubril spent more than 50 hours working under a microscope with a fine needle to expose its features. The animal measured just over 8 centimeters long and preserved a dorsal exoskeleton made up of a head shield and nine body segments.

These two regions had different functions. The head shield carried six pairs of appendages used for feeding and sensing. Beneath the body were plate-like respiratory structures that resemble the book gills seen in modern horseshoe crabs.

The First Clear Evidence of a Chelicera

The most striking feature is the chelicera, a pincer-like appendage that defines chelicerates. This structure separates spiders and their relatives from insects, which instead have antennae at the front of their bodies. Chelicerates rely on grasping appendages, often associated with venom delivery.

Despite the abundance of Cambrian fossils, no clear example of a chelicera from that period had been identified before. This discovery fills that gap and provides direct evidence of when these defining features first appeared.

Bridging a Major Evolutionary Gap

Before this fossil was studied, the oldest known chelicerates came from the Early Ordovician Fezouata Biota of Morocco, dating to about 480 million years ago. The new specimen predates them by 20 million years, placing M. cousteaui near the base of the chelicerate lineage.

It represents a transitional form, linking earlier Cambrian arthropods that seem to lack chelicera with later horseshoe crab-like species known as synziphosurines.

“Megachelicerax shows that chelicera and the division of the body into two functionally specialized regions evolved before the head appendages lost their outer branches and became like the legs of spiders today,” explained Ortega-Hernández, “it reconciles several competing hypotheses; in a way, everybody was partly right.”

Early Complexity in the Cambrian Explosion

This fossil captures a key moment in the evolution of chelicerates. It shows that important elements of their body plan were already established shortly after the Cambrian Explosion, a time when life was rapidly diversifying.

“This tells us that by the mid-Cambrian, when evolutionary rates were remarkably high, the oceans were already inhabited by arthropods with anatomical complexity rivaling modern forms,” Ortega-Hernández added.

Why Early Success Was Delayed

Even with these advanced features, chelicerates did not immediately dominate marine ecosystems. For millions of years, they remained relatively uncommon and were overshadowed by groups such as trilobites. Only later did they expand and eventually move onto land.

“A similar evolutionary pattern has been documented in other animal groups,” said Lerosey-Aubril. “This shows that evolutionary success is not only about biological innovation — timing and environmental context matter.”

From Overlooked Fossil to Major Discovery

The fossil was collected from the middle Cambrian Wheeler Formation in Utah’s House Range. It was discovered by avocational fossil collector Lloyd Gunther and donated to the Kansas University Biodiversity Institute and Natural History Museum in 1981. For decades, it remained part of a collection of seemingly ordinary specimens until Lerosey-Aubril chose to examine it as part of his research on early arthropods.

Named After Jacques Cousteau

The species name Megachelicerax cousteaui honors French explorer Jacques-Yves Cousteau. Lerosey-Aubril – who is also French – and Ortega-Hernández selected the name to recognize Cousteau’s efforts to highlight the beauty and vulnerability of marine life.

“Cousteau and his crew inspired generations to look beneath the surface,” said Lerosey-Aubril, “it seemed fitting to name this ancient marine animal after someone who changed the way we see ocean life.” Just as Megachelicerax cousteaui has changed how we view chelicerates.

A Group That Still Shapes the Modern World

Today, chelicerates include more than 120,000 species, from spiders and scorpions to mites, horseshoe crabs, and sea spiders. They occupy a wide range of environments on land and in water.

“For thousands of years, these animals have quietly existed among us, deeply influencing our lives from pop-culture to medical and agricultural contributions,” Ortega-Hernández concluded. “This fossil discovery sheds new light on their origins.”

The Lasting Value of Museum Collections

The researchers also emphasized the importance of scientific collections. Institutions such as the University of Kansas Biodiversity Institute and Natural History Museum preserve specimens for decades, allowing new insights to emerge as scientific understanding evolves. The authors highlighted the work of curators including B. Lieberman and J. Kimmig, whose efforts ensure these collections remain available for future discoveries.

“This is a huge step forward in the genetic treatment of deafness, one that can be life-changing for children and adults,” says Maoli Duan, consultant and docent at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Sweden, and one of the study’s corresponding authors.

Targeting the OTOF Gene

The trial included ten patients between the ages of 1 and 24 who were treated at five hospitals in China. All had a genetic form of deafness linked to mutations in a gene called OTOF. These mutations prevent the body from producing enough of the protein otoferlin, which is essential for sending sound signals from the inner ear to the brain.

Rapid Results After a Single Injection

To address this, researchers used a synthetic adeno-associated virus (AAV) to deliver a working version of the OTOF gene directly into the inner ear. The treatment was given as a single injection through a membrane at the base of the cochlea known as the round window.

The effects appeared quickly. Most patients began to regain some hearing within one month. After six months, all participants showed clear improvement. On average, the level of sound they could detect improved from 106 decibels to 52.

Strongest Gains Seen in Younger Patients

Children showed the most dramatic responses, especially those between the ages of five and eight. One seven-year-old girl regained nearly full hearing and was able to have everyday conversations with her mother just four months after treatment. At the same time, the therapy also produced meaningful improvements in adult patients.

“Smaller studies in China have previously shown positive results in children, but this is the first time that the method has been tested in teenagers and adults, too,” says Dr. Duan. “Hearing was greatly improved in many of the participants, which can have a profound effect on their life quality. We will now be following these patients to see how lasting the effect is.”

Treatment Found To Be Safe

The therapy was shown to be safe and well-tolerated. The most commonly reported side effect was a decrease in neutrophils, which are a type of white blood cell. No serious adverse reactions were observed during the follow-up period of 6 to 12 months.

Expanding Gene Therapy for Hearing Loss

“OTOF is just the beginning,” says Dr. Duan. “We and other researchers are expanding our work to other, more common genes that cause deafness, such as GJB2 and TMC1. These are more complicated to treat, but animal studies have so far returned promising results. We are confident that patients with different kinds of genetic deafness will one day be able to receive treatment.”

The research involved multiple institutions, including Zhongda Hospital at Southeast University in China. Funding came from several Chinese research programs as well as Otovia Therapeutics Inc., the company that developed the gene therapy and employs many of the researchers involved. A full list of disclosures and conflicts of interest is available in the published paper.

These findings provide new insight into age-related inflammation and help explain why something as simple as a cough can sometimes lead to hospitalization in older individuals.

Aging Lung Cells and Inflammation

To explore what changes in older lungs, researchers focused on fibroblasts, the structural cells that help maintain lung tissue. In experiments with young mice, they activated a stress signal typically linked to aging. This caused the lungs to develop clusters of inflamed cells, including some marked by the GZMK gene, which was first identified in severe COVID-19 cases. Scientists believe future treatments could target these cells to interrupt the harmful cycle known as inflammaging.

“We were surprised to see lung fibroblasts working hand-in-hand with immune cells to drive inflammaging,” said Tien Peng, MD, a professor of Medicine and a member of the Cardiovascular Research Institute and Bakar Aging Research Institute at UCSF. “It suggests new ways to intervene before patients progress to severe inflammation that can require intubation.”

Peng is the senior author of the study, published in Immunity on March 27. Nancy Allen MD, PhD, a clinical fellow in the Pulmonary and Critical Care Division in the UCSF Department of Medicine, is the first author.

Fibroblasts and the NF-kB Pathway

Fibroblasts play a key role in keeping the lungs’ airways and air sacs stable and functional. However, they are also known to contribute to inflammation in conditions such as COPD. The research team wanted to determine whether signals from these cells could disrupt otherwise healthy lungs.

They examined a pathway called NF-kB, which is commonly associated with aging-related diseases. When activated, fibroblasts signaled macrophages in the lungs to initiate an immune response. This response then drew additional immune cells from the bloodstream, including those marked by GZMK.

Although these GZMK cells were not effective at fighting infection, they were still able to damage lung tissue.

Immune Cell Clusters and Lung Damage

After these clusters of immune cells formed, the young mice developed severe symptoms when infected, resembling the response typically seen in older adults. When researchers used a genetic method to remove the GZMK cells, the mice were better able to tolerate the infection.

This finding suggests that aging lung tissue itself may be a major driver of harmful inflammation.

The researchers also examined lung tissue from older patients hospitalized with COVID-related ARDS (acute respiratory distress syndrome). These samples contained similar clusters of inflamed cells to those observed in the mice. Patients with more severe illness had a greater number of these clusters, while healthy donor lungs showed none.

“We saw during COVID that our most vulnerable patients no longer had the infection but still had persistent and devastating lung inflammation,” Peng said. “This circuit of dysfunction between lung and immune cells makes for a promising new therapeutic target.”