Publisher Health

During the past 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE) with researchers at the BU CTE Center at the forefront. While some sports organizations like the National Hockey League and World Rugby still claim their sports do not cause CTE, a new review of the evidence by the world’s leading CTE expert strengthens the case that repetitive head impact (RHI) exposure is the chief risk factor for the condition.
CTE became national news in the United States in 2007, but it wasn’t until 2016 that the National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB) criteria for the neuropathological diagnosis of CTE were published, and they were refined in 2021. Rare, isolated case studies reporting aberrant findings or using non-accepted diagnostic criteria have been disproportionately emphasized to cast doubt on the connection between RHI and CTE.
In a review article in the journal Acta Neuropathologica, Ann McKee, MD, chief of neuropathology at VA Boston Healthcare System and director of the BU CTE Center, stresses that now over 600 CTE cases have been published in the literature from multiple international research groups. And of those over 600 cases, 97 percent have confirmed exposure to RHI, primarily through contact and collision sports. CTE has been diagnosed in amateur and professional athletes, including athletes from American, Canadian, and Australian football, rugby union, rugby league, soccer, ice hockey, bull-riding, wrestling, mixed-martial arts, and boxing.
What’s more, 82 percent (14 of the 17) of the purported CTE cases that occurred in the absence of RHI, where up-to-date criteria were used, the study authors disclosed that families were never asked what sports the decedent played.
According to the researchers, despite global efforts to find CTE in the absence of contact sport participation or RHI exposure, it appears to be extraordinarily rare, if it exists at all. “In studies of community brain banks, CTE has been seen in 0 to 3 percent of cases, and where the information is available, positive cases were exposed to brain injuries or RHI. In contrast, CTE is the most common neurodegenerative disease diagnosis in contact and collision sport athletes in brain banks around the world. A strong dose response relationship is perhaps the strongest evidence that RHI is causing CTE in athletes,” she added.
“The review presents the timeline for the development of neuropathological criteria for the diagnosis of CTE which was begun nearly 100 years ago by pathologist Harrison Martland who introduced the term “punch-drunk” to describe a neurological condition in prizefighters,” explained McKee, corresponding author of the study. The review chronologically describes the multiple studies conducted by independent, international groups investigating different populations that found CTE pathology in individuals with a history of RHI from various sources.”
CTE is characterized by a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other diseases caused by tau protein.
Funding for this research was provided by the National Institute of Neurological Disorders and Stroke (U54NS115266; R01NS119651; U01 NS 086659), National Institute on Aging (P30AG13846; U19AG06875; R01AG062348; RF1AG057902; K01AG070326), Department of Veterans Affairs (101BX002466, 101BX004613, BX004349), the Nick and Lynn Buoniconti Foundation, Andlinger Foundation, National Football League (NFL) and World Wrestling Entertainment (WWE) through unrestricted gifts, the Mac Parkman Foundation, and the National Operating Committee on Safety for Sports Equipment (NOCSEA).

President Biden has endorsed “harm reduction,” which aims to cut down on overdoses by encouraging safer drug use. But the organizations carrying out that strategy are severely underfunded.OSCEOLA, Iowa — So many of Deborah Krauss’s friends and neighbors have died of drug overdoses during the pandemic that she said she felt as if she had been living inside of a dream. The longest she has gone without someone dying, she noted, is three weeks. Her calendar grew cluttered with funerals.“I lost count at 40,” she recalled on a recent evening in a Des Moines office as she organized supplies to help people consume drugs more safely. “And it just keeps happening.”The next day, Ms. Krauss was on the road, parked outside a Walmart in the small Iowa town of Osceola, her trunk brimming with boxes of syringes, fentanyl test strips and overdose-reversing medication. A former hair stylist, she recalled the stress of grooming an ex-boyfriend’s facial hair to make him presentable at his funeral after he died from an overdose in 2018.Ms. Krauss, 38, is one of the few practitioners in Iowa of a public health strategy known as “harm reduction,” a wide-ranging set of policies that President Biden and many federal and local health officials and physicians have made central to their efforts to curtail record-breaking overdose deaths. The strategy does not seek to cut people off from drug use. Instead, it aims to give them tools to use drugs in a safer manner, like the supplies in Ms. Krauss’s trunk.Ms. Krauss loosely oversees a network of hundreds of drug users who rely on her regular deliveries of supplies, calling and texting her when in need.Kathryn Gamble for The New York TimesIn his State of the Union address on Tuesday, Mr. Biden, the first president to endorse the strategy, highlighted the federal government’s attention to some of the core features of harm reduction work, including a provision in a recently enacted spending package that makes it easier for doctors to prescribe buprenorphine, an effective addiction medication that Ms. Krauss works to get to drug users. During his speech, Mr. Biden recognized the father of a 20-year-old from New Hampshire who died from a fentanyl overdose, citing the more than 70,000 Americans dying each year from the potent synthetic opioid.The father’s story, he said, was “all too familiar to millions of Americans.”But two years after Mr. Biden took office, with the nation’s drug supply increasingly complex and deadly, the practice of harm reduction remains underfunded and partially outlawed in many states. The work is often conducted by organizations that run syringe exchange programs, with workers like Ms. Krauss, a former methamphetamine user, functioning as brokers between drug users and the resources they need to manage their consumption. Those workers can face legal risk in the process.“I have a hard time seeing the light at the end of the tunnel,” Ms. Krauss said. “We’ve been hanging by a thread.”Ms. Krauss works for the Iowa Harm Reduction Coalition, one of the few harm reduction groups in the state. The coalition operates a syringe exchange program, which also routes drug users to medication-assisted treatment, where they receive drugs that can help manage cravings.Researchers at RTI International, a nonprofit research institute, estimate that there are only around 1,100 full-time workers nationwide like Ms. Krauss, aided by a cast of around 600 part-time staff members and roughly 2,000 volunteers. A national survey conducted by RTI found that the median annual budget of a syringe exchange program was roughly $100,000, far less than what is needed to cover salaries, supplies and travel expenses.Ms. Krauss with her daughter dropping off supplies in Osceola at the home of Dove Solomon, an opioid user who suffers from back pain.Kathryn Gamble for The New York TimesThe scale of the challenge facing those workers is vast: Over 100,000 Americans die each year from drug overdoses — one every five minutes, the White House estimates. Many of those who die are younger than 50.Critics of harm reduction have argued that the strategy takes a permissive stance toward drug use, signaling acceptance of dangerous substances without the ultimate goal of sobriety. Many Republicans and some prominent Democrats have expressed discomfort with at least some of the aims of the approach. Senator Charles E. Grassley, Republican of Iowa, said at a congressional hearing last year that he “worried that making drugs more accessible is what this administration calls drug control.”Fentanyl Overdoses: What to KnowCard 1 of 5Devastating losses.

A new method to grow single crystals and simultaneously control their growth orientation without melt processing has been discovered by Texas A&M University materials science and engineering doctoral graduate Dr. Hande Ozcan and Dr. Ibrahim Karaman, department head and Chevron Professor.
The discovery of this new crystal growth and orientation control method in solid-state was recently published in the journal Acta Materialia. The research paper focuses on growing large single crystals and their ability to change their crystallographic orientation. Crystallographic orientation describes the alignment of the crystals within a bulk specimen.
“We have been working on single crystals over the last three decades, but growing the crystals with melt processing and controlling their orientations has been quite challenging,” Karaman said. “The method Hande discovered now saves us a lot of time and provides more flexibility. There is more to explore; that’s what makes us excited about this new method.”
According to the research paper, controlling the size, shape and crystallographic orientation of single crystals is vital to exploit the desired properties. Ozcan said this method is important for applications that require materials with anisotropic properties.
“This mechanism allows these materials to change their orientation in solid-state without cumbersome and costly melt processing techniques. This is important because these materials exhibit different properties when they have different crystallographic directions,” Ozcan said.
For the first time, Ozcan has seen crystallographic orientations can be changed at this large scale.

“This could fundamentally change how we look at single crystals and manipulate materials properties, because with solid-state methods, we can not only grow large single crystals very easily, but at the same time, we can now play with their crystallographic orientation,” Ozcan said.
Single crystals are essential to microelectronics, optical crystals, magnetic devices, solar cells, piezoelectric components and multifunctional alloys. One specific use case example for these materials is multifunctional shape memory alloys. These materials can change their shape and recover upon applying heat or stress.
“For example, you can deform the material when you apply a load, but when you release it, it returns to its original shape,” Ozcan said.
These properties strongly depend on the orientation of the single crystal; some orientations exhibit this recovery in a perfect fashion, and some do not. Thus, the orientation control is critical in obtaining superior functional properties.
Another advantage to this technique, according to the research paper, is that it does not require complex and expensive equipment.

Traditionally, melt-growth techniques, called the Bridgman and Czochralski processes, are used to obtain large crystals with a preferred orientation. However, controlling the crystal orientation is still challenging.
These methods rely on the availability of proper seed crystals, precise nucleation and thermal profile control during processing.
Because of this complexity, these methods are very expensive. The new method is called the solid-state crystal growth (SSCG) technique, a method where large bulk crystals with different crystallographic orientations could be made with simple heat treatments.
In this process, the crystals produced are more versatile and can achieve better chemical homogeneity than in the traditionally used melt-growth techniques.
The research team at Texas A&M demonstrated the SSCG method in two alloy systems, FeMnAlNi and CuMnAl, and achieved repeated, massive orientation changes in the solid state.
These findings offer a new strategy for manipulating the orientation of large single crystals on demand to take advantage of their superior and highly anisotropic properties, according to the research paper.
“This process works with materials that have semicoherent precipitates and that have two-phase regions in their phase diagram,” Ozcan said. “When you cycle the material from high to low temperatures in a two-phase region multiple times, precipitates nucleate and dissolve and leave subgrain boundaries behind. Then the grains start to grow, decreasing the excess subgrain boundary energy. These grains continue to grow and merge, and finally, you can get a single crystal.”
When you continue to cycle the material after it becomes a single crystal, there are no other ways to reduce the excess energy in the system, and it activates a mechanism that changes its crystallographic orientation.
“We actually discovered this technique while we were working on something else. We were not specifically targeting to change the crystallographic orientation,” Ozcan said. “We were just working on growing large single crystals.”
During that process, Ozcan and the team found that in just a few cycles, the alloys would turn into single crystals, and with additional cycles, she realized that the orientation of the single crystals started to change completely.
“I showed the results to Dr. Karaman, and I was so excited,” she said. “After that, we started understanding what was going on and why the crystal orientation was changing; we tried different methods and processing schedules in order to manipulate this change.
This discovery will open up extensive research areas, she said. This is just the beginning of this exciting new path of finding new materials.

Trikafta’s U.S. list price is over $322,000 a year. That is nearly 60 times the annual salary of a minimum wage earner in Turkey, where the government wanted to import a generic version made in Argentina. Vertex sued and blocked it.Vertex has brought in $17 billion from Trikafta since 2019. An analysis by researchers in Britain found that a year’s supply of the drug could be manufactured for just $5,700.The company says it is working to increase access to the drug globally.

The brain floats in a sea of fluid that cushions it against injury, supplies it with nutrients and carries away waste. Disruptions to the normal ebb and flow of the fluid have been linked to neurological conditions including Alzheimer’s disease and hydrocephalus, a disorder involving excess fluid around the brain.
Researchers at Washington University School of Medicine in St. Louis created a new technique for tracking circulation patterns of fluid through the brain and discovered, in rodents, that it flows to areas critical for normal brain development and function. Further, the scientists found that circulation appears abnormal in young rats with hydrocephalus, a condition associated with cognitive deficits in children.
The findings, available online in Nature Communications, suggest that the fluid that bathes the brain — known as cerebrospinal fluid — may play an underrecognized role in normal brain development and neurodevelopmental disorders.
“Disordered cerebrospinal fluid dynamics could be responsible for the changes in brain development we see in children with hydrocephalus and other developmental brain disorders,” said senior author Jennifer Strahle, MD, an associate professor of neurosurgery, of pediatrics, and of orthopedic surgery. As a pediatric neurosurgeon, Strahle treats children with hydrocephalus at St. Louis Children’s Hospital. “There’s a whole host of neurologic disorders in young children, including hydrocephalus, that are associated with developmental delays. For many of these conditions we do not know the underlying cause for the developmental delays. It is possible that in some of these cases there may be altered function of the brain regions through which cerebrospinal fluid is circulating.”
Much research has been conducted mapping the drainage of cerebrospinal fluid in the brains of adults. However, it is not well known how cerebrospinal fluid interacts with the brain itself. Cerebrospinal fluid pathways in the brain likely vary with age, as young children have not yet developed the mature drainage pathways of adults.
Strahle; first author Shelei Pan, an undergraduate student; and colleagues developed an X-ray imaging technique using gold nanoparticles that allowed them to visualize brain circulation patterns in microscopic detail. Using this method on young mice and rats, they showed that cerebrospinal fluid enters the brain through small channels primarily at the base of the brain, a route that has not been seen in adults. In addition, they found that cerebrospinal fluid flows to specific functional areas of the brain.
“These functional areas contain specific collections of cells, many of which are neurons, and they are associated with major anatomic structures in the brain that are still developing,” Strahle said. “Our next steps are to understand why cerebrospinal fluid is flowing to these neurons specifically and what molecules are being carried in the cerebrospinal fluid to those areas. There are growth factors within the cerebrospinal fluid that may be interacting with these specific neuronal populations to mediate development, and the interruption of those interactions could result in different disease pathways.”
Further experiments showed that hydrocephalus reduces cerebrospinal fluid flow to distinct neuron clusters. Strahle and colleagues studied a form of hydrocephalus that affects some premature infants. Babies born prematurely are vulnerable to brain bleeding around the time of birth, which can lead to hydrocephalus and developmental delays. Strahle and colleagues induced a process in young rats that mimicked the process in premature babies. After three days, the tiny channels that carry cerebrospinal fluid from the outer surface of the brain into the middle were fewer and shorter, and circulation to 15 of the 24 neuron clusters was significantly reduced.
“The idea that cerebrospinal fluid can regulate neuronal function and brain development isn’t well explored,” Strahle said. “In the setting of hydrocephalus, it’s common to see cognitive dysfunction that persists even after we successfully drain the excess fluid. The disordered cerebrospinal fluid dynamics to these functional regions of the brain may ultimately affect brain development, and normalizing flow to these areas is a potential approach to reducing developmental problems. It is an exciting field, and we are only at the beginning of understanding the diverse functions of cerebrospinal fluid.”

A single oral dose of the antibiotic azithromycin can reduce the risk of postpartum sepsis and death among women who deliver vaginally by one-third, according to a large multi-country clinical trial funded by the National Institutes of Health. Only 1.6% of women in the study who received azithromycin during labor developed sepsis or died within six weeks after delivery, compared to 2.4% of those who received placebo. Azithromycin did not reduce the risk of stillbirth, newborn sepsis or newborn death.
Results from the study, which enrolled more than 29,000 women in seven low- and middle-income countries, were published today in the New England Journal of Medicine and presented at the Society for Maternal-Fetal Medicine’s 43rd Annual Pregnancy Meeting, San Francisco.
“These findings have the potential to change clinical practice by providing a safe, effective and low-cost approach to reduce the global burden of maternal sepsis and death,” said Diana W. Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the primary funder of the trial. “We urgently need effective strategies to prevent pregnancy-related infections, which account for roughly 10% of maternal deaths worldwide.”
The trial, called A-PLUS, was co-funded by the Bill & Melinda Gates Foundation through a grant to the Foundation for the National Institutes of Health, a non-profit organization that manages multinational research projects implemented through alliances with public and private institutions in support of the NIH mission. NICHD’s Global Network for Women’s and Children’s Health Research conducted the study.
Sepsis — a life-threatening complication of bacterial and other infections — is a leading cause of maternal and newborn deaths worldwide, especially in low- and middle-income countries. Azithromycin, an inexpensive antibiotic effective against a broad range of bacteria, is known to reduce maternal infection when given intravenously during cesarean delivery. Two small studies have suggested that giving the oral version of the drug to women who plan to deliver vaginally may reduce maternal or neonatal infection and death.
Launched in 2020, A-PLUS enrolled women at NICHD Global Network sites in Bangladesh, the Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan and Zambia. Between September 2020 and August 2022, 29,278 participants planning to deliver vaginally were randomly assigned to receive either a two-gram dose of oral azithromycin or a placebo during labor.
Within the first six weeks after delivery, 227 of 14,526 participants (1.6%) who received azithromycin developed sepsis or died, compared to 344 of 14,637 (2.4%) in the placebo group. Deaths were rare in both groups. Sepsis occurred in 219 participants in the azithromycin group (1.5%) and 339 in the placebo group (2.3%). Additionally, women who received azithromycin were less likely to develop endometritis (infection of the lining of the womb) and other infections. They also had fewer hospital readmissions and unscheduled healthcare visits, compared to the placebo group.
“Leveraging the infrastructure and expertise of the NICHD Global Network across three continents allowed us to rapidly gather these important data. We hope that our findings will be applied to help improve maternal care in low- and middle-income countries around the globe,” said Alan T.N. Tita, M.D., Ph.D., associate dean of Global and Women’s Health of the University of Alabama at Birmingham (UAB) Marnix E. Heersink School of Medicine.
The trial was co-led by Dr. Tita and Waldemar A. Carlo, M.D., also of UAB. Eight U.S. academic institutions and RTI International, Research Triangle Park, North Carolina, which serves as the data coordinating center for the NICHD Global Network, collaborated with eight international partners on A-PLUS.
Stillbirth, newborn sepsis or death within the first four weeks of life occurred with comparable frequencies in the azithromycin and placebo groups. Overall, these adverse events occurred for 10.5% of births in the azithromycin group and 10.3% in the placebo group.
A-PLUS was originally designed to enroll up to 34,000 women. However, based on a recommendation from the study’s independent data and safety monitoring committee following a planned interim data analysis, the study was stopped early due to the clear maternal benefit of azithromycin.

Why do some people get ADHD, while others do not? And how early in life or in the womb is the seed of ADHD sown?
Researchers from Aarhus University have come closer to answering this question in a large study, which has just been published in the journal Nature Genetics.
Together with national and international partners, the researchers have studied more than six million genetic variants in 38,691 people with ADHD and 186,843 people without ADHD. By this means it has been possible to identify 27 genetic risk variants for the common neurodevelopmental disorder.
Risk genes are expressed in the brain and neurons
The study is ground-breaking, inter alia because it finds more than twice as many risk variants as previous studies have identified.
The term “genetic variants” means specific variations in the DNA code — in this case, variants which are observed more frequently in people with ADHD than in people without the diagnosis. Variants in DNA affect, for example, the degree to which a gene is expressed and subsequently the amount of protein that is encoded by the gene.

By linking the genetic variants — i.e. the variations in DNA — to specific genes, the researchers have gained new knowledge about which tissues and cell types are particularly affected in individuals with ADHD. The study is based on data from the Danish iPSYCH cohort, deCODE Genetics in Iceland and the Psychiatric Genomics Consortium.
Subsequently, the researchers combined the results with existing data on gene expression in different tissues, cell types and brain development stages, and they discovered that genes involved in ADHD have a particularly high level of expression in a wide range of brain tissues and early in brain development — in fact already at the embryonic stage.
“This emphasises that ADHD should be seen as a brain developmental disorder, and that this is most likely influenced by genes that have a major impact on the brain’s early development,” says Professor Ditte Demontis of the Department of Biomedicine at Aarhus University, who is first author of the study.
In addition, the researchers found that the genetics that increase the risk of ADHD particularly affect genes that are expressed in neurons, especially dopaminergic neurons.
“This is interesting because dopamine plays a role in relation to the reward response in the brain, and because a frequently used form of ADHD medicine works by increasing the concentration of dopamine in different brain regions. Our results indicate that the imbalance in dopamine in the brains of people with ADHD is partly attributable to genetic risk factors,” says Ditte Demontis.

Associated with reduced concentration capacity and short-term memory
ADHD is influenced by many common genetic variants, each of which increases the risk slightly, says the professor.
In fact, with the help of advanced statistical models, the researchers have estimated that there are around 7,300 common genetic variants that increase the risk of ADHD. It is particularly interesting that the vast majority of these variants — 84-98 percent — also have an influence on other mental disorders, e.g. autism, depression and schizophrenia.
It has previously been shown that risk variants for ADHD can affect a person’s cognitive abilities.
To investigate this further, the researchers analysed data from an independent dataset, consisting of 4,973 people who had undergone extensive neuro-cognitive tests. By using information from the new study about which variants increase the risk of ADHD, they found in the independent data set that an increased load of ADHD risk variants in the genome of an individual is associated with reduced reading and mathematical abilities, reduced attention and reduced short-term memory.
“The results increase our knowledge of the biological mechanisms underlying ADHD, and they point to specific genes, tissues and cell types involved in ADHD. This knowledge can be used as a starting point for further studies of the disease mechanisms and identification of new drug targets,” explains Ditte Demontis.
And the study must be followed up, she emphasises.
“We have only mapped a small fraction of the common variants that influence ADHD — just 27 of the 7,300 that potentially exist. So there is a need for larger genetic studies,” she says.
International cross-disciplinary collaboration is the way forward
Large international collaborations are crucial to identifying the genetic causes of psychiatric diseases and neurodevelopmental disorders, because to do so requires studies of tens or hundreds of thousands of people with these conditions. Just as in the current ADHD study, there are often 100 or more researchers involved, with different areas of expertise, such as genetics, psychiatry, psychology, epidemiology, molecular biology, statistics, bioinformatics and computer science.
“In order to understand more of the genetic and biological mechanisms, it is important to have even larger studies, involving more people with ADHD,” says Professor Anders Børglum of the Department of Biomedicine, Aarhus University, who is the last author of the study and one of the research directors of the Danish iPSYCH project.
“But it is also important to undertake studies that focus on identifying how the genetic risk variants perturb biological processes in the brain cells (the neurons), and their way of joining up and communicating with each other in the brain. For the latter, both brain cells and early developmental stages of the brain, so-called mini-brains or brain organoids, are currently being examined” he says.

In a first of its kind randomized controlled trial an international team of researchers led by the Butler Columbia Aging Center at the Columbia University Mailman School of Public Health shows that caloric restriction can slow the pace of aging in healthy adults. The CALERIE™ intervention slowed pace of aging measured from participants’ blood DNA methylation using the algorithm DunedinPACE (Pace of Aging, Computed from the Epigenome). The intervention effect on DunedinPACE represented a 2-3 percent slowing in the pace of aging, which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention. The results are published online in the journal Nature Aging.
“In worms, flies, and mice, calorie restriction can slow biological processes of aging and extend healthy lifespan” says senior author Daniel Belsky, PhD, associate professor of epidemiology at Columbia Mailman School and a scientist with Columbia’s Butler Aging Center. “Our study aimed to test if calorie restriction also slows biological aging in humans.”
The CALERIE™ Phase-2 randomized controlled trial, funded by the US National Institute on Aging, is the first ever investigation of the effects of long-term calorie restriction in healthy, non-obese humans. The trial randomized 220 healthy men and women at three sites in the U. S. to a 25 percent calorie-restriction or normal diet for two years.  CALERIE™ is an acronym for ‘Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy’.
To measure biological aging in CALERIE Trial participants, Belsky’s team analyzed blood samples collected from trial participants at pre-intervention baseline and after 12- and 24-months of follow-up. “Humans live a long time,” explained Belsky, “so it isn’t practical to follow them until we see differences in aging-related disease or survival. Instead, we rely on biomarkers developed to measure the pace and progress of biological aging over the duration of the study.” The team analyzed methylation marks on DNA extracted from white blood cells. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with aging.
In the primary analysis Belsky and colleagues focused on three measurements of the DNA methylation data, sometimes known as “epigenetic clocks”. The first two, the PhenoAge and GrimAge clocks, estimate biological age, or the chronological age at which a person’s biology would appear “normal”. These measures can be thought of as “odometers” that provide a static measure of how much aging a person has experienced. The third measure studied by the researchers was DunedinPACE, which estimates the pace of aging, or the rate of biological deterioration over time. DunedinPACE can be thought of as a “speedometer”.
“In contrast to the results for DunedinPace, there were no effects of intervention on other epigenetic clocks,” noted Calen Ryan, PhD, Research Scientist at Columbia’s Butler Aging Center and co-lead author of the study. “The difference in results suggests that dynamic ‘pace of aging’ measures like DunedinPACE may be more sensitive to the effects of intervention than measures of static biological age.”
Our study found evidence that calorie restriction slowed the pace of aging in humans” Ryan said.  “But calorie restriction is probably not for everyone. Our findings are important because they provide evidence from a randomized trial that slowing human aging may be possible. They also give us a sense of the kinds of effects we might look for in trials of interventions that could appeal to more people, like intermittent fasting or time-restricted eating.”
A follow-up of trial participants is now ongoing to determine if the intervention had long-term effects on healthy aging. In other studies, slower DunedinPACE is associated with reduced risk for heart disease, stroke, disability, and dementia.  “Our study of the legacy effects of the CALERIE™ intervention will test if the short-term effects observed during the trial translated into longer-term reduction in aging-related chronic diseases or their risk factors,” says Sai Krupa Das, a senior scientist and CALERIE investigator who is leading the long-term follow up of CALERIE™ participants.
DunedinPACE was developed by Daniel Belsky and colleagues at Duke University and the University of Otago. To develop DunedinPACE, researchers analyzed data from the Dunedin Longitudinal Study, a landmark birth cohort study of human development and aging that follows 1000 individuals born in 1972-73 in Dunedin, New Zealand. Researchers first analyzed the rate of change in 19 biomarkers across 20 years of follow-up to derive a single composite measure of the Pace of Aging. Next, the researchers used machine-learning techniques to distill this 20-year Pace of Aging into a single-time-point DNA methylation blood test. The values of the DunedinPACE algorithm correspond to the years of biological aging experienced during a single calendar year, providing a measure of the pace of aging.
The study was supported by US National Institute on Aging grant R01AG061378 and also utilized resources provided by the CALERIE Research Network (R33AG070455) and the Dunedin Study (R01AG032282). Coauthors received additional support from the American Brain Foundation, and NIH grants P30AG028716, R01AG054840, R33AG070455, CIHR RN439810, R01 AG071717, R03AG071549 U01AG060906.

Researchers have calculated the carbon footprint for the full life cycle of fertilisers, which are responsible for approximately five percent of total greenhouse gas emissions — the first time this has been accurately quantified — and found that carbon emissions could be reduced to one-fifth of current levels by 2050.
The researchers, from the University of Cambridge, found that two thirds of emissions from fertilisers take place after they are spread on fields, with one third of emissions coming from production processes.
Although nitrogen-based fertilisers are already known to be a major source of greenhouse gas emissions, this is the first time that their overall contribution, from production to deployment, has been fully quantified. Their analysis found that manure and synthetic fertilisers emit the equivalent of 2.6 gigatonnes of carbon per year — more than global aviation and shipping combined.
Carbon emissions from fertilisers urgently need to be reduced; however, this must be balanced against the need for global food security. Earlier research has estimated that 48% of the global population are fed with crops grown with synthetic fertilisers, and the world’s population is expected to grow by 20% until 2050.
The Cambridge researchers say that a combination of scalable technological and policy solutions are needed to reduce fertiliser emissions while maintaining food security. However, they estimate that if such solutions could be implemented at scale, the emissions from manure and synthetic fertilisers could be reduced by as much as 80%, to one-fifth of current levels, without a loss of productivity. Their results are reported in the journal Nature Food.
“Incredibly, we don’t actually know how many chemicals we produce globally, where they end up, where and how they accumulate, how many emissions they produce, and how much waste they generate,” said co-author Dr André Cabrera Serrenho from Cambridge’s Department of Engineering.

Serrenho and his co-author Yunhu Gao undertook a project to accurately measure the total impacts of fertilisers, one of the two main products of the petrochemical industry. Of all the products made by the petrochemical industry, the vast majority — as much as 74% — are either plastics or fertilisers.
“In order to reduce emissions, it’s important for us to identify and prioritise any interventions we can make to make fertilisers less harmful to the environment,” said Serrenho. “But if we’re going to do that, we first need to have a clear picture of the whole lifecycle of these products. It sounds obvious, but we actually know very little about these things.”
The researchers mapped the global flows of manure and synthetic fertilisers and their emissions for 2019, along all stages of the lifecycle, by reconciling the production and consumption of nitrogen fertilisers and regional emission factors across nine world regions.
After completing their analysis, the researchers found that unlike many other products, the majority of emissions for fertilisers occur not during production, but during their use.
“It was surprising that this was the major source of emissions,” said Serrenho. “But only after quantifying all emissions, at every point of the lifecycle, can we then start looking at different mitigation methods to reduce emissions without a loss of productivity.”
The researchers listed and quantified the maximum theoretical impact of different mitigation methods — most of these are already known, but their maximum potential effect had not been quantified.

Emissions from the production of synthetic fertilisers are mostly from ammonia synthesis, partly due to chemical reactions used in the production process. The most effective mitigation at the production stage would be for the industry to decarbonise heating and hydrogen production. Additionally, fertilisers could be mixed with chemicals called nitrification inhibitors, which prevent bacteria from forming nitrous oxide. However, these chemicals are likely to make fertilisers more expensive.
“If we’re going to make fertilisers more expensive, then there needs to be some sort of financial incentive to farmers and to fertiliser companies,” said Serrenho. “Farming is an incredibly tough business as it is, and farmers aren’t currently rewarded for producing lower emissions.”
The single most effective way to reduce fertiliser-associated emissions, however, would be to reduce the amount of fertilisers that we use. “We’re incredibly inefficient in our use of fertilisers,” said Serrenho. “We’re using far more than we need, which is economically inefficient and that’s down to farming practices. If we used fertiliser more efficiently, we would need substantially less fertiliser, which would reduce emissions without affecting crop productivity.”
The researchers also looked at the mix of fertilisers used around the world, which varies by region. The researchers say that replacing some of the fertilisers with the highest emissions, such as urea, with ammonium nitrate worldwide could further reduce emissions by between 20% and 30%. However, this would only be beneficial after decarbonising the fertiliser industry.
“There are no perfect solutions,” said Serrenho. “We need to rethink how we produce food, and what sorts of economic incentives work best. Perhaps that means paying farmers to produce fewer emissions, perhaps that means paying more for food. We need to find the right mix of financial, technological and policy solutions to reduce emissions while keeping the world fed.”
Serrenho and Gao estimate that by implementing all the mitigations they analysed, emissions from the fertiliser sector could be reduced by as much as 80% by 2050.
“Our work gives us a good idea of what’s technically possible, what’s big, and where interventions would be meaningful — it’s important that we aim interventions at what matters the most, in order to make fast and meaningful progress in reducing emissions,” said Serrenho.
The research was part of the C-THRU project, led by Professor Jonathan Cullen, where researchers from four UK and US Universities are working to bring clarity to the emissions from the global petrochemical supply chain.