Tag: Medication

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Genome Wide Analysis Broadens Genetic Knowledge of Anxiety

A large European meta-analysis led by King’s College London has revealed 39 new areas of the genome linked to symptoms of anxiety and provided new estimates of heritability of this common condition.

Writing in Nature Human Behaviour, the researchers explain they found 80 variants linked to anxiety in 74 specific areas of the genome, but 35 were already known to be linked to the disorder from previous research.

“These correlations highlight the interconnection between mental and physical health,” said Brittany Mitchell, PhD, a senior researcher at the QIMR Berghofer medical research institute and co-first author on the study in a press statement.

“Importantly, while some shared genetic variants may increase risk for both a physical health condition and more severe anxiety symptoms, it’s also true that living with chronic pain or illness can contribute to anxiety symptoms. Our findings don’t reveal causation or the direction of effect, but they do open up important questions for future research.”

Anxiety disorders are very common mental health conditions across the globe with large variations in severity from mild to debilitating. Previous research has attempted to assess the genetic heritability of anxiety but estimates of how heritable this condition is vary widely.

In this study, genetic data from 14 cohorts of people with generalized anxiety symptoms assessed via self-report questionnaires between 2007 and 2023 was combined to carry out a large meta-analysis of 693,869 people. Most of the cohorts were largely made up of people of European ancestry, for example, the UK Biobank, and mostly came from Europe or North America.

In addition to finding the new variants, the team also created a polygenic risk score for anxiety aggregating genome-wide SNP effects. Overall, the estimated SNP-based heritability was around 6% and the team estimated that about 1-3% of variance in anxiety symptom severity could be attributed to genetics according to the polygenic risk score.

Notably the research also highlighted some links between the genetics of anxiety and other conditions like irritable bowel syndrome, coronary artery disease, and migraine.

“Given the high and rising rates of anxiety, especially in young adults, it is more important than ever to improve our ability to identify and understand sources of risk,” write the authors.

“Despite its public health impact, progress in anxiety genetics lags behind other major mental health conditions. We hope our findings encourage genome-wide investigations leveraging existing but potentially underutilized anxiety severity data in genotyped cohorts, accelerating our progress in understanding the genetic architecture of anxiety.”

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David Sinclair plans to test whole-body rejuvenation drugs in the XPrize competition

The outspoken longevity scientist David Sinclair has been predicting that one day, you’ll go to the doctor and get a prescription that will make you 10 years younger.

Now MIT Technology Review has learned that he has plans to launch human tests of an oral “reprogramming” drug as part of a $101 million competition organized by the XPrize Foundation. 

The foundation is offering cash awards to teams able to “restore” a person to an earlier apparent age, as measured by improvements in immune, cognitive, and muscle function. 

The grand prize goes to any team able to show a 10-year (or greater) relative improvement after one year of treatment. 

Reached by phone, Sinclair, a biologist at Harvard Medical School, confirmed that he plans to give an oral drug mixture to volunteers in a bid to seek “evidence for age restoration in humans.”

The trial, if it goes forward, will be a significant new development in the race to harness so-called epigenetic reprogramming. That technology is based on the discovery, 20 years ago, of powerful genes able to turn an adult cell into a stem cell similar to those found in embryos.

The age-reversal effect is believed to occur via a resetting of molecular controls on DNA known as epigenetic marks, which help determine a cell’s overall metabolism and identity.

Companies are now racing to use that phenomenon for a new form of rejuvenation medicine. Only this January, one of Sinclair’s companies, Life Biosciences, made news by winning approval to launch an initial human trial using a set of powerful reprogramming genes. The company announced today it had treated its first patient. 

But that test involves a complex gene therapy and is limited to patients’ eyes, where it could treat conditions like glaucoma. 

Sinclair’s new plan is bolder: a reprogramming drug you’d swallow in order to promote such effects across the body. 

“What we’re aiming to do is to epigenetically restore the animal and eventually the person,” he says. “It is true that we’ve been doing extensive animal studies with the oral agent and are looking to compete in the XPrize.”

This alternative method, chemical reprogramming, uses drugs to mimic the effects of the embryonic genes. That is significant because drug compounds can travel through the bloodstream, reaching most or all cells in a person’s body. 

Some experts expressed caution, saying the chemical process, at least as used in labs, is extremely harsh and not even particularly effective. “Who doesn’t dream of whole-body rejuvenation? I think it’s a great goal,” says Sergiy Velychko, founder of Soxogen, a stealth reprogramming company in Boston. “But these chemicals are used in very, very high concentrations for cell reprogramming.”

Sinclair declined to describe the exact makeup of the drug candidate, code-named SL-100, calling its contents “highly, highly confidential.”

However, he has previously published lab studies of what he called “epigenetic age-reversal cocktails,” which mixed powerful chemicals with known supplements and commercially available medicines. 

It’s those latter components that would be easiest to test on people, since doctors are free to prescribe them, even for unusual objectives like age reversal. James Clement, head of Betterhumans, an organization that specializes in life-extension studies using existing drugs, said in a message that he is “running clinical trials” of an oral reprogramming cocktail for Sinclair’s XPrize team.

Sinclair’s team is competing in the XPrize Healthspan Competition, launched in 2023. It follows several previous competitions that focused on commercial spaceflight, lunar landings, and other goals. The XPrize Foundation is led by executive chairman Peter Diamandis, also an active promoter of longevity research.

“If two teams are equivalent, they would split the award,” says Jamie Justice, a doctor and executive director for the contest, which was bankrolled by Saudi Arabia’s Hevolution Foundation, “But it will be incredibly hard to even get to one winner.”

Justice says a judging panel is now in the process of picking 10 finalists from 65 teams that have been exploring health foods, lifestyle interventions, digital trackers, and drug compounds. 

Sinclair’s team, Justice says, was a late entrant to the contest, but like all teams, it would be required to move into wider human tests starting this year. “You have to be ready and in trials,” she says.

The race to harness the reprogramming phenomenon and apply it to living people is heating up, even outside the XPrize competition. On June 2, a startup called NewLimit, founded by the crypto billionaire Brian Armstrong, said it had raised a further $435 million, from investors including Peter Thiel’s Founders Fund, to support what it calls “age reprogramming.” 

The company says it is working toward delivering genetic reprogramming instructions to the liver, to treat diseases of that organ.

But Sinclair has been saying that whole-body rejuvenation is a possibility too. And for that, chemicals, rather than gene therapy, could be the most practical strategy. 

Sinclair says his lab has been searching for such compounds and is starting to use AI “to improve the oral agents that we’re testing.”

Chemical reprogramming cocktails, as used in labs, typically involve a mix of vitamins, approved drugs, and experimental molecules. For instance, one recipe Sinclair filed a patent on includes the supplement forskolin,  the antidepressant tranylcypromine, and an experimental chemical, laduviglusib, which has been tested against Alzheimer’s, among other ingredients.

“In those days it was a six-factor cocktail,” Sinclair says of his earlier research. “But we’ve come a long way. I can’t disclose what’s in it, but it’s an improvement and an advance on that, and we’ve done a number of animal studies. They are not published, but we’ve been doing them for a long time, and we want to make sure that we’ve done a full investigation of safety and efficacy before we release any of the data.”

While Sinclair’s results aren’t published, other teams say attempts to reverse the age of entire animals using chemical drugs haven’t worked yet. Last year, the lab of Vadim Gladyshev, another Harvard biologist and a member of a different XPrize team, reported on its attempt to rejuvenate mice by installing pumps in their bodies that released controlled doses of seven compounds.

Gladyshev says the procedure proved to be toxic. “The idea was to see if we could rejuvenate whole animals. Unfortunately, we have not found [the right] conditions,” he says. “At low concentrations there was no effect, and high concentrations were toxic.”

Gladyshev says he doesn’t know what is in Sinclair’s cocktail, but says that “trying to improve the combinations makes sense.”

Sinclair, who is the author of several books on aging and has a large social media following, has frequently been criticized by other scientists for making unproven rejuvenation claims. 

In 2024, he resigned as president of the Academy for Health and Lifespan Research after claiming that a supplement developed by a company his brother runs had “reversed” the age of dogs, a claim for which there was so little evidence that one scientist called it a “lie.”

Part of the problem is that scientists still disagree on how to measure aging. And they don’t have a reliable way to measure age reversal, either, should it ever be achieved.

Justice, the XPRIZE director, says a primary purpose of the competition is to solve that problem by encouraging the development of standardized measures of aging. That is so that anti-aging drugs can be assessed reliably, and, one-day, approved by regulators if they work.

 “We as a scientific field have been forced to ask, ‘If a medicine improves how we age, how would we know?” Justice said during a public meeting with FDA officials in May. “If something worked, what would convince us as scientists, what’s meaningful to the general public?”

Finalists in the Healthspan competition will be announced in August.

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Defective HIV RNA Linked to Persistent Viremia During Long-Term ART

Antiretroviral therapy (ART) has enabled most people living with HIV to live long and healthy lives. However, a small portion of people experience detectable traces of the virus, known as nonsuppressible viremia (NSV), despite strict adherence to long-term treatment regimens and the absence of symptoms. The results of a study headed by researchers at Johns Hopkins University School of Medicine now suggest that most cases of NSV are explained by defective and noninfectious copies of the virus.

The study, which involved more than 50 people, found that while traces of HIV-1 RNA can persist in blood after optimal therapy, cases of non-suppressible viremia are driven by HIV-1 RNA with defects in a piece of the RNA known as 5’-leader. The team developed a digital PCR (dPCR) assay, CLAWS (Capturing 5′ Leader Anomalies Without Sequencing), that distinguishes intact from defective 5′L RNA.

“From a clinical perspective, this is important because people with HIV are taught that the absolute goal of their medication is to achieve undetectable viral load, and they worry,” said Francesco R. Simonetti, MBChBD, PhD, an assistant professor of medicine in the Division of Infectious Diseases at Johns Hopkins University School of Medicine. The new findings, said Simonetti and his team, should provide relief to many people living with HIV who fear a viral rebound or who are concerned about transmitting the virus to partners despite taking effective treatment.

Simonetti is senior and corresponding author of the team’s report in Nature Communications (“5′ leader defects drive persistent HIV-1 viremia on long-term ART”), in which they stated, “These findings identify 5′L-defective genomes as the predominant driver of NSV and establish CLAWS as a practical tool for monitoring viremia in clinical and cure-related settings.”Modern antiretroviral therapies, which date back to 1996, prevent HIV from infecting new populations of immune system cells, but aren’t able to retroactively prevent previously infected cells from releasing HIV viral particles. Since those cells usually represent a small portion of infected cells after a person is on stable therapy, most people with HIV (PWH) who take antiretroviral therapies are able to bring their viral loads to clinically undetectable levels in their blood.

However, in some cases, which are estimated to occur less than 1% of the time, people may experience clinically detectable levels after taking long-term antiretroviral drug therapy. “Traces of HIV-1 RNA can persist in plasma despite long-term suppressive antiretroviral therapy (ART), the authors stated. This could happen years later, or, in less frequent cases, they may have never achieved undetectable levels. “The sources of NSV remain poorly defined, in part due to limited tools to characterize plasma HIV-1 RNA,” the team continued. “NSV raises concerns for virologic failure, transmission, and immune activation, complicates ART management, causing anxiety and ultimately affecting the quality of life of PWH.”

For the newly reported study, the investigators examined blood samples from 52 people living with HIV who had detectable loads of the virus despite taking long-term antiretroviral drug therapy. These samples, which were assessed from 32 people and compared to an additional 20 samples, were collected between 2021 and 2025. The majority of participants were white men, between ages 58 and 68, and received care in the United States, Canada, and Denmark. The researchers found that most detectable forms of the virus, around 95%, were due to defective copies, and most defects were due to mutations or deletions in the 5’-leader region of HIV-1 RNA. This region is known to orchestrate the production of copies of the virus, but in this case, the defects prevented the generation of infectious virus.

“In 31 participants from the original NSV cohort and an additional 20 participants from the validation cohort, RNA transcribed from defective proviruses accounted for a median of 95% of plasma HIV-1 RNA, firmly establishing their central role in persistent viremia,” the investigators wrote in summary.

The study offers evidence that clinicians can now study the virus in blood plasma and confirm if clinically detectable levels are due to defective copies released from one or a few T-cell clones, said Simonetti. If so, he added, this could eliminate the need for extra medications and could prevent related complications. It could also help people living with HIV have access to surgeries or other procedures, such as hip or knee replacements or organ transplants, and participate in clinical studies if they know they have HIV under control.

“We know that these defective proviruses cannot infect new cells, but they are still clinically relevant,” said Simonetti. “Think of how many extra visits, extra drugs, extra costs, and tests they’ve been causing. It’s also clear from the new study that, over time on treatment, intact proviruses that make virus are pruned away, while defective ones escape the immune system,” he said. “Now we want to understand these differences in immune recognition to uncover HIV’s vulnerabilities.”

Similar to using a liquid biopsy to detect cancer mutations in DNA, the CLAWS assay developed by the researchers uses advanced technology to identify detectable viral loads that are due to defective copies. The method is cost-effective and can be broadly used in HIV clinics and research settings.

In their paper, the authors wrote in conclusion, “In summary, our results establish 5’L-defective proviruses as the major source of NSV and introduce CLAWS as a practical tool for dissecting persistent viremia. Beyond clarifying mechanisms of HIV-1 persistence, CLAWS provides immediate translational utility for clinical monitoring and HIV-1 cure research.”

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Cortical On/Off Switch Provides Sleep Benefits to Awake Mice

Researchers have demonstrated that key restorative functions of sleep can be triggered in localized regions of the awake brain, providing new insights into why sleep is essential for learning and memory.

The NIH-funded study, led by investigators at the University of Wisconsin–Madison, showed that artificially inducing sleep-like patterns of neural activity in specific brain regions of sleep-deprived mice restored memory performance and reduced the need for subsequent sleep in those areas. The findings, published in Nature Neuroscience, suggest that the characteristic activity patterns of non-rapid eye movement (NREM) sleep, not simply reduced brain activity, play a central role in maintaining healthy neural circuits.

The work offers a new window into the biological mechanisms that allow sleep to refresh the brain and may eventually inform non-invasive approaches to combat cognitive impairment associated with sleep loss.

A closer look at sleep’s restorative role

Researchers have long shown that sleep is essential for memory formation and learning, but the precise mechanisms underlying these benefits remain incompletely understood.

During NREM sleep, which accounts for approximately 80% of adult sleep, the brain undergoes extensive reorganization. Connections between neurons, known as synapses, are selectively strengthened, maintained, or weakened. This process is thought to secure important memories while preventing neural networks from becoming overloaded with information accumulated during wakefulness.

Previous studies from the laboratory of senior author Chiara Cirelli, MD, PhD, found that sleep-deprived animals and humans occasionally exhibit brief episodes of localized slow-wave activity, the characteristic electrical pattern of NREM sleep, even while remaining awake. These observations raised the possibility that small portions of the brain might temporarily enter a sleep-like state independently of the rest of the brain.

The question remained whether a more sustained version of this phenomenon could reproduce some of sleep’s restorative effects.

Inducing local sleep while animals remain awake

To investigate, the researchers developed an experimental system that allowed them to generate sleep-like activity in targeted regions of the brain without causing the animals to fall asleep.

Using genetically modified mice equipped with light-sensitive neural circuits, the team delivered rhythmic pulses of light that produced alternating periods of neuronal activation and silence. These oscillations closely resembled the “on-off” firing patterns observed during NREM sleep.

The stimulation was applied to one hemisphere of the brain in sleep-deprived mice for 30-minute periods while the animals remained awake and responsive to their environment.

Cirelli compared the phenomenon to a strategy observed in nature.

“What we’re essentially doing is forcing sleep in a local region of the brain,” she said. “While that part is solidifying memories and restoring learning capacity, other parts stay aware/vigilant and connected to environment.”

She noted that dolphins exhibit a related behavior, sleeping with one cerebral hemisphere at a time while the other remains awake.

Reduced need for recovery sleep

The researchers found that brain regions receiving the sleep-like stimulation subsequently displayed lower levels of slow-wave activity during natural sleep.

Slow-wave activity is widely considered a measure of sleep pressure, the biological drive to sleep that accumulates during wakefulness. Reduced slow-wave activity suggested that the stimulated brain regions had already undergone part of the restorative process normally achieved during sleep.

The results challenged a longstanding hypothesis that sleep’s benefits primarily arise from globally reducing neuronal firing rates to relieve fatigue.

Instead, the study found that restoration depended specifically on the rhythmic alternation between active and inactive states characteristic of NREM sleep. Simply suppressing neuronal activity was insufficient.

The findings suggest that the temporal structure of neural activity during sleep may be more important than the overall amount of activity.

Restoring memory after sleep deprivation

To determine whether the induced sleep-like activity produced meaningful behavioral benefits, the researchers evaluated the animals using a tactile memory task that normally depends on adequate sleep.

Sleep-deprived mice typically perform poorly on this type of test, reflecting impaired memory consolidation and reduced learning capacity.

However, sleep-deprived mice that received bilateral stimulation of sensory and motor brain regions performed nearly as well as animals that had not been deprived of sleep. In contrast, sleep-deprived mice that did not receive stimulation showed significantly impaired performance.

These results suggest that localized sleep-like activity can compensate for at least some of the cognitive deficits caused by sleep loss.

Understanding how the brain resets

The work provides new support for the concept that sleep serves as a form of neural recalibration.

Throughout wakefulness, experiences continuously modify synaptic connections, increasing the strength and number of neural links. Without a mechanism to rebalance these networks, the brain could eventually lose efficiency, consume excessive energy, and struggle to encode new information.

NREM sleep appears to provide a structured period during which these connections are selectively refined. The current study indicates that the characteristic slow oscillations of NREM sleep may be the critical driver of this process.

By recreating these oscillations in isolated brain regions, researchers were able to trigger aspects of the reset mechanism without requiring the entire brain to enter sleep.

Potential implications for human health

Although the experiments relied on invasive genetic and optical techniques that are not currently applicable to humans, the investigators believe the findings may inform future therapeutic strategies.

The next step will be determining whether similar effects can be achieved using non-invasive approaches such as transcranial brain stimulation, which can modulate neural activity through the scalp.

If successful, such methods could eventually help mitigate cognitive deficits associated with sleep deprivation, shift work, aging, or neurological disorders.

“This research further decodes why we sleep and how we learn, which brings us a step closer to understanding how to better prevent and treat cognitive decline,” said Amy Bany Adams, PhD, acting director of the NIH’s National Institute of Neurological Disorders and Stroke.

While a replacement for sleep remains firmly out of reach, the study reveals that some of sleep’s most important restorative processes may be far more localized, and potentially more controllable, than previously appreciated.

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GLP-1 Drugs Linked to Lower Rates of Substance Use Disorders

A study led by researchers at the University of Texas at El Paso (UTEP) has found that people with type 2 diabetes or obesity who were prescribed GLP-1 receptor agonists (GLP-1 RAs) had substantially lower odds of developing alcohol, opioid, nicotine, and cocaine use disorders compared with similar individuals who were not taking the medications. The research, published in the journal Frontiers in Psychiatry, used health data from more than 142,000 patients from the All of Us Research Program and adds to a growing body of evidence indicating that GLP-1 medications may have an influence on dopamine signaling and other neural pathways that drive cravings not just for food but other substances.

“Our findings add to growing evidence that GLP-1 medications may influence more than appetite and blood sugar regulation,” said lead author Tadesse Abegaz, PhD, an assistant professor in the School of Pharmacy, University of Texas at El Paso. “These medications appear to affect brain pathways involved in reward and craving, which could help explain the lower rates of substance use disorders observed in our study.”

Substance use disorders are a significant public health challenge contributing to illness, premature death, and higher healthcare costs. While current treatment methods that combine medications and behavioral therapy can be effective, relapse rates remain high, often exceeding 50% within the first year after treatment, suggesting a need for additional ways to treat this disease.

An emerging candidate for this are GLP-1 receptor agonists such as semaglutide and liraglutide. Developed to treat type 2 diabetes and obesity, these drugs have drawn attention because GLP-1 receptors are found not only in areas involved in metabolic regulation but also in brain regions associated with reward and reinforcement.

“Animal studies have demonstrated that GLP-1 RAs reduce the self-administration of alcohol, opioid, nicotine, and cocaine effects [that] are believed to be mediated through interactions with the mesolimbic dopamine system,” the researchers wrote. Small human studies and observational analyses have also suggested reductions in substance cravings, relapse rates, and alcohol-related hospitalizations among some patients receiving GLP-1 therapies.

The El Paso investigators said they initiated their research to move beyond smaller studies because “the real-world impact of GLP-1 RA on multiple co-occurrence of SUD (substance use disorder) has not been systematically investigated.”

To address this gap, the team conducted a retrospective nested case-control study using data from the NIH’s All of Us Research Program. The study examined individuals with type 2 diabetes or obesity and identified cases involving new diagnoses of alcohol use disorder, opioid use disorder, nicotine use disorder, or cocaine use disorder. These individuals were compared with matched control participants who had diabetes or obesity but no documented history of substance use disorders.

Analyses of these data showed consistent associations across all categories studied. GLP-1 receptor agonist use was associated with a 74% reduction in the odds of alcohol use disorder, a 69% reduction in the odds of opioid use disorder, a 68% reduction in the odds of nicotine use disorder, and a 75% reduction in the odds of cocaine use disorder. The researchers also reported 75% lower odds of any substance use disorder among GLP-1 users compared with non-users.

“Exposure to GLP-1 RAs was consistently associated with significantly reduced odds of SUD cases,” the researchers wrote. “These findings suggest that GLP-1 RAs may exert behavioral-modifying effects that extend beyond glycemic control and weight loss.”

The researchers noted that their research was observational and does not establish cause and effect. “We do not support prescribing these medications for addiction treatment at this time,” said senior author Gabriel Frietze, PhD, an assistant professor of pharmaceutical sciences at UTEP. “Because this was an observational study in a specific clinical population, randomized clinical trials are needed before GLP-1 medications can be recommended for treating addiction.”

The team believes the findings could help guide future approaches to addressing substance use-related health issues by identifying biological pathways that may be targeted therapeutically. The authors noted that mechanisms potentially involved include modulation of dopamine release, suppression of neuroinflammation, and attenuation of stress-related neural circuits.

“Our next goal is to conduct prospective research that follows individuals initiating GLP-1 therapy over time,” Abegaz said. “We aim to evaluate whether changes in the substance use behaviors occur after treatment begins and whether these changes related to improvements in mental health and quality of life. Ultimately, this work will help inform whether GLP-1 medications could become part of future treatment strategies for substance use disorders.”

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