Nothing lives forever, but compared to other cells in the body, hematopoietic stem cells (HSCs) are remarkably long-lived. HSCs are blood-forming cells — they give rise to rapidly dividing progenitor cells, which in turn generate hundreds of billions of cells to fulfill the daily demand of oxygen-delivering red blood cells, disease-fighting white blood cells and clot-forming platelets.
HSCs typically remain dormant within the bone marrow, yet they possess the ability to activate and replenish blood cells continuously, maintaining a relatively youthful profile throughout the life of an organism. What is the secret of long-lived HSCs that wards off the effects of aging? A team led by researchers at Baylor College of Medicine revealed in Nature Cell Biology that the enzyme cyclophilin A, which is produced in large amounts in HSCs, is key for these cells to retain their regenerative potential and avert the effects of aging.
Long live the stem cells!
“A driving force of cellular aging is the accumulation of proteins that have reached the end of their useful life,” said corresponding author Dr. André Catic, assistant professor and CPRIT Scholar in Cancer Research in the Huffington Center on Aging at Baylor. “With age, proteins tend to misfold, aggregate and accumulate inside the cell, which leads to toxic stress that can disrupt cell function.”
Cells that frequently engage in cell division, like progenitor cells, can dispose of protein aggregates through dilution. On the other hand, long-lived HSCs, which do not divide often, face the problem of the accumulation of misfolded proteins and subsequent toxic stress. Nevertheless, HSCs remain impervious to aging. How do they do it?
“Understanding the molecular mechanisms that contribute to HSC aging not only contributes to the field of normal HSC biology, but also may have significant clinical relevance for cancer treatment,” said co-first author of the work, Dr. Lauren Maneix, who was at the Catic lab while working on this project.
Molecular chaperones at work
Previous studies have shown that mammalian cells express several hundreds of molecular chaperones, proteins that preserve or change the three-dimensional conformation of existing proteins. Cyclophilins, one of the most abundant chaperones, have been implicated in the aging process. However, how they affect cellular proteins has not previously been studied.

Working with mice, the researchers first characterized the protein content of HSCs and discovered that cyclophilin A is a prevalent chaperone. Further experiments showed that the expression of cyclophilin A was significantly decreased in aged HSCs, and genetically eliminating cyclophilin A accelerated natural aging in the stem cell compartment. In contrast, reintroducing cyclophilin A into aged HSCs enhanced their function. Together, these findings support cyclophilin A as a key factor in the longevity of HSCs.
Connecting cyclophilin A, intrinsically disordered proteins and HSC longevity
Next, the team investigated the proteins with which cyclophilin A interacts, preserving their stability. “We found that proteins enriched in intrinsically disordered regions are frequent targets of the chaperone,” Catic said.
Intrinsically disordered proteins naturally change their 3-D conformation to interact with different proteins, nucleic acids or other molecules. Consequently, proteins rich in intrinsically disordered regions regulate many cellular processes by promoting specific activities between molecules. “Due to their flexible nature, intrinsically disordered proteins are inherently prone to aggregation. Cyclophilin A supports these proteins in fulfilling their functions and simultaneously prevents them from clumping,” Catic said.
Furthermore, the findings suggest that cyclophilin A interacts with intrinsically disordered proteins from the moment of their synthesis. “As these proteins are being made, cyclophilin A makes sure they keep the appropriate conformations and are maintained at sufficient levels,” Catic said. “Genetic depletion of cyclophilin A results in stem cells distinctively lacking intrinsically disordered proteins.”
“For the first time, our study showed that producing disordered proteins and maintaining the structural diversity of the proteins in a cell plays a role in HSC aging,” Maneix said.
Co-first author Polina Iakova, Charles G. Lee, Shannon E. Moree, Xuan Lu, Gandhar K. Datar, Cedric T. Hill, Eric Spooner, Jordon C. K. King, David B. Sykes, Borja Saez, Bruno Di Stefano, Xi Chen, Daniela S. Krause, Ergun Sahin, Francis T. F. Tsai, Margaret A. Goodell, Bradford C. Berk and David T. Scadden also contributed to this study.

Published4 hours agoShareclose panelShare pageCopy linkAbout sharingThis video can not be playedTo play this video you need to enable JavaScript in your browser.By Gemma DunstanWales LiveWheelchair user Kat Watkins has said a doctor assumed she was not having sex because of her disability. The 37-year-old from Swansea said she was also told she was “a very odd shape” by the consultant while having a smear test. She is one of more than 30 adults who told BBC Wales Live they have faced barriers to healthcare due to their disabilities. The Welsh government said it was “very disappointing” to hear these stories.Due to her condition, osteogenesis imperfecta – which creates brittle bones – Ms Watkins said gaining proper healthcare is almost impossible.She said she now avoids seeking medical attention due to her “traumatic” past experiences. “I’ve been fighting for the last 37 years to get through barriers and they’re still there. So for me they’re more than just barriers, it is a constant battle,” she said.Boy, 7, died from Aids after doctor ignored rules Family wants tougher pub rules after cellar fall deathDisabled woman made 1,000 calls for Ed Sheeran ticketsMs Watkins described the smear test, saying the consultant recommended cancelling them in the future as she was not sexually active at the time.”He was making the assumption that I wasn’t having sex because I’m a disabled person,” she said.Despite telling staff the best way to position her body, she said they also treated her like a “textbook example”, rather than as an individual. It meant she had to revisit several times until they were able to obtain a result.During another visit to hospital she said she felt she was not listened to or believed by staff when she told them she had broken several bones in her leg – it was later confirmed that it was broken in five places. “I got a letter back to say the doctor had done everything correctly and they couldn’t see any problems,” she said.”I was heartbroken, I was completely dismissed – all my feelings were dismissed.”Swansea Bay health board said it could not comment on individual cases but it would be happy to discuss Ms Watkins’s concerns with her. ‘I was failed completely’Michelle Penny has never had a smear test due to lack of access and, like Ms Watkins, she feels failed by the healthcare system.”I just hope and pray that nothing is going wrong, I’m crossing my fingers and hoping for the best,” said the 39-year-old.She has been left almost bedbound by Myalgic encephalomyelitis and struggles to leave home to attend medical appointments. “Everyone needs healthcare of some type, but if you can’t get to them then you’re failed completely,” she said. Ms Penny has not seen a GP in around six years, and has routine asthma appointments over the phone – but says it is not satisfactory. “You could tell them anything they’d have to believe you because they can’t see you,” she added.She has backed calls for at-home tests to detect for HPV, which are currently undergoing a trial in England. Other examples people shared with Wales Live include: A man said that, during a fit he couldn’t control, he heard staff say he was doing it on purposeA women said a lack of ways to contact her surgery puts her off contacting them after it recently took 339 attempts to get through on the phonelineA deaf woman claimed she had her BSL interpreters cancelled by a hospital, as they had seen her speak and so assumed she could lip readA women said private tests confirmed that new symptoms weren’t a part of her existing disability after NHS doctors insisted that they wereAlex Harrison, disability equality officer at Disability Wales, said that many people who have “battles” with healthcare simply disengage from it. “As a result they say they have new impairments or conditions have worsened,” she said.Wales has the highest proportion of disabled people in the UK at 26%, according to the organisation, and Ms Harrison said communication is a common barrier many can face to healthcare services.”Many feel like they’ve just been ignored or are too much work to engage with,” she said. “We hear so much that people are just waiting and waiting for contact and then it never coming.”She believes disability equality training, “delivered by a disabled person”, and more opportunity for feedback is needed to create change.A Welsh government spokesperson said: “It’s very disappointing to hear these stories and we expect people with disabilities to be listened to and treated respectfully when they access NHS services.”Our Disability Rights Taskforce is working with disabled people and organisations to make recommendations to improve the lives of disabled people in Wales.”More on this storyWoman too young for adapted home stuck in hospitalPublished26 October 2023Disabled woman’s 1,000 calls for Ed Sheeran ticketPublished12 February 2023

Published40 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, PA MediaBy Jim ReedHealth reporterA final compensation scheme for infected blood victims could be running by the year’s end after the government made a key concession in the Lords.Ministers accepted a Labour amendment to the Victims and Prisoners bill, meaning the scheme must be set up within three months of the law passing.The deputy Lords leader said victims had waited “far too long for justice”.But Earl Howe warned the creation of the new body could be disrupted if Parliament were dissolved or adjourned.Westminster is due to rise at the end of July for the summer recess, and a general election is widely expected to take place this autumn.’Worst treatment disaster’More than 30,000 NHS patients were given contaminated blood products in the 1970s and 80s in what has been called the worst treatment disaster in the history of the health service.It is thought around 3,000 later died, after contracting HIV or hepatitis C from a treatment made from blood plasma or a blood transfusion.The government has said there is a moral case for compensating victims and, in November 2022, made the first interim payments of £100,000 each to around 4,000 surviving victims and bereaved partners. Campaigners say the speed compensation is paid out is crucial. It has been estimated that one person infected by the contaminated treatments dies every four days. What is the infected blood scandal and how many people died?The stories behind the infected blood scandalBBC iPlayer – BBC Wales Investigates – Blood MoneyIn April 2023, the chair of the ongoing public inquiry into the scandal, Sir Brian Langstaff, called for a full compensation scheme to be set up immediately. He also recommended interim payments should be extended to some of the children and parents of those who had died.In December 2023, opposition MPs and Conservative rebels forced through a key vote in the Commons designed to speed up the creation of a new body to administer and run the scheme, the first parliamentary defeat for Rishi Sunak as prime minister.More recently the government has been accused of trying to “wriggle out” of the new time limit by proposing its own amendments to the legislation in the Lords.Faced with the possibility of losing another vote, ministers agreed to a Labour-led demand for the final compensation system to be in place within three months of the Victims and Prisoners Bill becoming law.Speaking at the bill’s report stage, the Conservative peer Lord Howe said: “The government shares the determination of the House to ensure compensation reaches victims quickly.”He added: “We recognise that Parliament and the infected blood community need clarity on when these measures will be in place.”Nick Thomas-Symonds, Labour’s shadow minister without portfolio, said the decision marked “another important victory” for the victims of the scandal.”The government has now been forced, under cross-party pressure, to set out a clear timetable to deliver a final compensation scheme,” he said. “They must now progress – urgently – with getting the body ready to make payments.”The public inquiry into the infected blood scandal has been running since 2018 and is expected to publish its final report and recommendations on 20 May. More on this storyWhat is the infected blood scandal and how many people died?Published2 AprilChildren used as ‘guinea pigs’ in clinical trialsPublished18 April

The move would kick off a lengthy rule-making process and would amount to a major change in federal policy.The Justice Department plans to forward a recommendation for easing restrictions on marijuana to the White House in what could amount to a major change in federal policy, according to three people familiar with the matter.Even though the move, which if approved would kick off a lengthy rule-making process, does not end the criminalization of the drug, it would be a significant shift in how the government views the safety and use of marijuana for medical purposes.It could also lead to the softening of other laws and regulations that account for the use or possession of cannabis, including sentencing guidelines, banking and access to public housing.One person familiar with the recommendation, speaking on the condition of anonymity, said Attorney General Merrick B. Garland would tell the White House Office of Management and Budget on Tuesday that the government should change the drug’s classification.For more than half a century, marijuana has been considered a so-called Schedule I drug, classified on the same level as highly addictive substances like heroin that the Drug Enforcement Administration describes as having no currently accepted medical use.Last year, the Health and Human Services Department recommended to the D.E.A. that marijuana should be a Schedule III drug, which would put it alongside less addictive substances like Tylenol with codeine, ketamine and testosterone, meaning that it would be subject to fewer restrictions on production and research, and that it could be taken with a prescription.The Associated Press earlier reported the decision.Ashley Southall

Proteins are the workhorses of life. Organisms use them as building blocks, receptors, processors, couriers and catalysts. A protein’s structure is critical to its function. Malformed proteins not only fail to carry out their tasks, they can accumulate and eventually gum up the inner workings of cells. As a result, misfolded proteins cause a variety of degenerative diseases, from Alzheimer’s and Parkinson’s to the blinding disease retinitis pigmentosa. These disorders are currently incurable.
A paper out of UC Santa Barbara reveals a new connection between a particular ion transport protein and the cell’s garbage disposal, which grinds up misfolded proteins to stave off their toxic accumulation. The results, published in Developmental Cell, identify a target for treating these debilitating conditions.
“By studying basic cell biology in fruit fly ovaries, we stumbled upon a way to prevent neurodegeneration, and we think this has potential applications in the treatment of some human diseases,” said senior author Denise Montell, Duggan Professor and Distinguished Professor in the Department of Molecular, Cellular, and Developmental Biology.
For 35 years, Montell’s lab has studied the movement of cells in fruit fly ovaries. It might seem esoteric, she is the first to admit, but it provides a fantastic model for cell mobility. “And cell movement underlies embryonic development, drives wound healing and contributes to tumor metastasis,” she explained. “So it’s a really fundamental cell behavior that we care to understand deeply.”
The setting and characters
The star of this paper is a gene called ZIP7, which encodes a protein of the same name. In previous work, Montell’s team came across a mutation in this gene that impaired cell mobility, piquing their interest.
The ZIP7 protein ferries zinc ions within a cell. These ions are exceedingly rare within the cytoplasm but abundant in proteins where they often form part of the architecture and catalyze chemical reactions. “ZIP7 is conserved in evolution from plants to yeast to flies to humans,” Montell said. “So it’s doing something really fundamental, because it’s been around for a really long time.”
ZIP7 is also the only zinc transporter found in the endoplasmic reticulum, a membranous structure where a cell makes proteins destined for the outer membrane of the cell or for secretion out of the cell. About a third of our proteins are made here.

If ZIP7 is our protagonist, then misfolded proteins and their disposal are the theme of the study. For proteins, function follows form. It’s not enough to have the right ingredients, a protein must fold correctly to function properly. Misfolded proteins are responsible for a host of diseases and disorders.
But proteins will sometimes misfold even in a healthy cell. Fortunately, cells have a quality control system to deal with this eventuality. If the error is small, the cell can try folding it again. Otherwise, it will tag the misfolded molecule with a small protein called ubiquitin and send it out of the endoplasmic reticulum (ER) for recycling.
Waiting in the cytoplasm are structures called proteasomes, the “garbage disposals” of the cell. “It literally chews up the protein into little pieces that can then be recycled,” Montell said.
“But if the garbage disposal gets overwhelmed — somebody puts too many potato peels in there — then the cell experiences ER stress.” This triggers a response that slows down protein synthesis (pauses our potato prep) and produces more proteasomes so that the system can clear the backlog of waste. If all this fails, the cell undergoes programmed death.
The plot thickens
Co-lead author Xiaoran Guo, Montell’s former Ph.D. student, saw that loss of ZIP7 caused ER stress in the fruit fly’s ovary. So she set out to determine if this stress was the reason the cells lost their mobility. Indeed, inducing ER stress with a different misfolded protein also impaired cell migration.

When Guo over-expressed ZIP7 in these cells, the backlog of misfolded proteins disappeared, the ER stress vanished, and the cells regained their mobility. “I was so surprised that I had to question myself if I had done everything correctly,” Guo said. “If this was real, just ZIP7 alone must be very potent in resolving ER stress.”
What’s more, the misfolded protein she used, called rhodopsin, contains no zinc in its structure. This led Guo to suspect that ZIP7 must be involved somewhere in the degradation pathway. Co-lead author, and fellow doctoral student, Morgan Mutch used a drug to block the proteasome from degrading misfolded rhodopsin and observed that this negated the beneficial effect of ZIP7. She concluded that ZIP7 must be acting somewhere before the proteasome munches up the misfolded protein.
The authors created four modified ZIP7 genes: two mutations disrupted the protein’s ability to carry zinc, while the other two left this unchanged. They discovered that zinc transport was critical in reducing ER stress.
At this point, a new character enters our story: the enzyme Rpn11, which forms part of the proteasome. Much like trying to stuff a large head of broccoli down the disposal, misfolded proteins with ubiquitin tags don’t fit into the proteasome. Rpn11 snips off these tags, enabling the misfolded protein to slip into the proteasome core for disassembly. Zinc is essential forRpn11 to catalyze the removal of ubiquitin.
“I was very surprised, and then excited, when I saw that increasing ZIP7 expression almost completely prevented the buildup of those ubiquitin-tagged proteins,” Mutch said. “We were expecting the opposite result.”
Mutch determined that ZIP7 was critical in supplying zinc to Rpn11, enabling it to trim the tags that label defective proteins so that they fit into the structure that actually breaks them down. Blocking the Rpn11 enzyme confirmed this hypothesis.
“That feeling when you discover something new, something no one has figured out before, is the best feeling for a scientist,” Mutch added.
A potential therapy
The results suggest that overexpressing ZIP7 could form the basis for treating a variety of diseases. For instance, misfolded rhodopsin causes retinitis pigmentosa, a congenital blinding disease that is currently untreatable. Scientists already have a strain of fruit flies with the mutation that causes a similar disease, so the team overexpressed the ZIP7 gene in these flies to see what would happen.
“We found that it prevents retinal degeneration and blindness,” Montell said. Every single one of the flies with mutant rhodopsin usually develops retinitis pigmentosa, but a full 65% of those with overactive ZIP7 formed eyes that respond normally to light.
Montell’s lab is now collaborating with Professor Dennis Clegg, also at UC Santa Barbara, to further investigate the effect of ZIP7 in human retinal organoids, tissue cultures that bear a mutation that causes retinitis pigmentosa. This project was originally funded by the National Institute for General Medical Sciences. For the next three years it will be supported by a $900,000 grant from the Foundation Fighting Blindness so Montell, Clegg and their colleagues can test the hypothesis that ZIP7 gene therapy will prevent blindness in retinitis pigmentosa patients.
What’s more, proteasome capacity declines as we get older, contributing to many classic signs of aging and increasing the probability of age-related degenerative diseases. Therapies targeting ZIP7 could potentially slow the development or progression of these ailments, as well. They’ve already yielded promising results extending fruit fly lifespan.
“This is a poster child for fundamental, curiosity-driven research,” Montell said. “You’re just studying something because it’s cool, and you follow the data and end up discovering something you never set out to study, possibly even a cure for multiple diseases.”

Currently, most therapies for allergic diseases require lifelong treatment. Allergic reactions, characterized by ongoing (type 2) inflammation in response to chronic antigen exposure, underlie many chronic diseases in humans, including asthma, atopic dermatitis, ulcerative colitis and more. T helper 2 (Th2) cells play an important role in the body’s immune response, particularly in allergic reactions. Despite their central role, the sustained activity of Th2 cells during allergic reactions, even in the face of constant antigen exposure, has long puzzled researchers.
A research team that included authors from Mass General Brigham, including members Brigham and Women’s Hospital, Massachusetts General Hospital, and Mass Eye and Ear, embarked on a quest to understand the diversity and cellular mechanisms of human Th2 cells. By conducting gene expression analyses of inflamed tissues, they pinpointed a subset of Th2 cells called Th2-MPP cells. Their findings suggested that these cells might serve as precursors to several crucial Th2 cell populations responsible for disease symptoms. These discoveries lay the groundwork for therapeutic interventions targeting these cells, potentially offering relief to patients living with allergic diseases. Results are published in Nature Immunology.
The research team created a single cell transcriptomic atlas, a comprehensive database of genes that are turned “on” and “off” in individual cells in the body, using inflamed tissues from patients with nine different chronic allergic diseases. They used this atlas to identify Th2-multipotent progenitor (Th2-MPP) cells, which chronically expressed two transcription factors, TCF7 and LEF1. These transcription factors allowed Th2-MPP cells to exhibit characteristics similar to stem cells in cancer and chronic infection, acting as progenitor cells that can give rise to other kinds of cells. The team also performed detailed studies on Th2 cells from nasal tissue in patients with chronic rhinosinusitis. They found that Th2-MPP cells could be the precursor for multiple types of Th2 cells that cause disease symptoms.
“We still have much to learn about the contribution of progenitor cells to chronic human inflammation, but we are hopeful that the study of this area of immunity could provide opportunities for future disease-modifying therapeutic approaches,” said senior author Patrick Brennan, MD, PhD, a physician-researcher in the Brigham Division of Allergy and Clinical Immunology.
“Our work suggests that Th2-MPP cells have the potential to sustain type 2 inflammation in the face of chronic antigen exposure and lays the foundation for further investigation to better understand their contribution to disease,” said lead author Radomir Kratchmarov, MD, a research fellow in the Brigham Division of Allergy and Clinical Immunology.

The grazing of both domestic and wild animals is shaping landscapes across Europe. It can also contribute to multiple ecosystem services, such as providing habitat for biodiversity. Grazing systems with lower densities of animals and with minimal and only targeted applications of deworming and other medicinal treatments offer benefits for local biodiversity protection and various ecosystem services. However, this type of land management also poses a range of challenges, leading to a constant decline in the number of land users engaged in low-intensity grazing. A team of researchers led by iDiv, UL, and UFZ set out to investigate these challenges and potential interventions in eight European case studies. Between 2019 and 2021, they conducted 74 face-to-face interviews with farmers, landowners, livestock owners, and managers of a rewilding area with semi-wild herbivores, like wild ponies or semi-wild cattle.
Land users rely on subsidies, but money is not everything
The researchers focused on the motivation and challenges driving decision-making among all land users engaged in low-intensity grazing practices. This was despite economic considerations becoming increasingly important as land users’ revenue-generating activities are no longer sufficient to cover the rising cost of equipment, rent, and taxes.
“Money is not everything. Many of the land users we interviewed practice this type of grazing management because they think it is good, not out of economic motivation,” says first author Dr Julia Rouet-Leduc. Rouet-Leduc led the project as a former doctoral researcher at iDiv and UL and is now a postdoctoral researcher at the Stockholm Resilience Centre. Caring for nature and, in some cases, also the desire to maintain traditional agricultural practices were important aspects of the land users’ motivation. For example, a land user working with wild ponies in Galicia (Spain) shared: “The main reason for the maintenance of this system is that people … love the ponies; they ‘have a fever’, and this tradition runs very deeply in their hearts.”
The researchers found that many land users struggle with rules and regulations that are incompatible with low-intensity grazing management. For example, rules to mark or tag livestock — an extremely challenging task when animals are allowed to graze freely in large areas — were perceived as limiting. Land users also felt that the policies in place, especially the Common Agricultural Policy of the European Commission (CAP), were holding back nature-friendly and sustainable practices. For example, a land user in Romania noted that farmers were required to remove scrubs from their pastures or they would otherwise not be eligible for subsidies or even have to pay penalties. However, scrubs have important ecosystem functions, such as providing shade in the summer and as an additional food resource in the winter. In general, the CAP was perceived as too restrictive, and many land users chose not to apply for subsidies at all. “By not applying for CAP support, we have the freedom to really see what suits the local ecosystem,” a Belgian land user stated.
Rural exodus is putting traditional labour at risk
The interviews also showed that many land users struggle with socio-economic changes in the countryside. The so-called ‘Rural Exodus’ is leading to a lack of workforce, while physical work is still very much needed, especially for work with cattle or horses. “The next generation does not want to farm because it is too hard, too much work,” a land user from Lithuania said. “They usually move abroad and choose easier career options’.’

“The CAP could support farmers in High Nature Value farming regions and put incentives in place to preserve or restore extensive grazing systems,” senior author Dr Guy Pe’er, a senior researcher at UFZ and iDiv, suggests. “It’s not a lack of budgets but rather the lack of ambition to support sustainable farming.”
More flexibility and improved market access needed
The researchers used the interviews to derive and suggest interventions to encourage better grazing practices. “What is needed is more flexibility for land users,” Rouet-Leduc says. “Current policies are, for the most part, not encouraging such practices, and particularly not offering a level playing field for land users.” While the EU’s CAP offers important economic support, it also drives counter-productive management due to problematic requirements, she adds. Additional financial incentives could improve the support for more sustainable grazing management, according to the study’s authors. Especially in areas where land has been abandoned, there can be opportunities for rewilding large herbivores, which ultimately provide multiple ecosystem services. However, such systems require flexibility since they differ from management approaches with domestic animals.
The researchers also call for better labelling and certification for environmentally friendly grazing practices to increase public support and to help develop markets for such products. Some of the interviewed land users felt that market access could be improved by supporting direct marketing, for example, via farm shops.
“There are clearly real challenges for farmers, and they are not easy to overcome,” Pe’er explains in light of ongoing farmers’ demonstrations in countries like Germany, Poland, and Italy. “But removing environmental standards will not help land users. They need a package that includes an ambitious CAP reform, providing real support for farmers who need it to be more sustainable; the Nature Restoration Law to improve the standards of good management; and a framework for sustainable food systems to improve the market options for sustainable farming.”

In a new study published in Cell Stem Cell, USC scientists report significant progress in cultivating nephron progenitor cells (NPCs), the cells destined to form the kidney’s filtration system, the nephrons. NPCs hold immense promise for understanding kidney development, modeling diseases, and discovering new treatments.
“By enhancing our capability to grow NPCs from human stem cells, we create a new avenue for understanding and combating congenital kidney diseases and cancer,” said corresponding and lead author Zhongwei Li, an assistant professor of medicine, and stem cell biology and regenerative medicine at the Keck School of Medicine of USC.
In the study, funded in part by the National Institutes of Health, Li Lab postdocs Biao Huang and Zipeng Zeng and their collaborators improved the chemical cocktail for generating and growing NPCs in the laboratory.
This improved cocktail enables the sustained growth of both mouse and human NPCs in a simple 2-dimensional format. This marks a major improvement over the previous 3-dimensional system, which was not only more cumbersome, but also limited the ability to perform genome editing on the cells.
The cocktail also enables the expansion of induced NPCs (iNPCs) from human pluripotent stem cells. These iNPCs closely resemble native human NPCs. With this approach, iNPCs can be generated from any individual starting with a simple blood or skin biopsy. This approach will facilitate the creation of patient-specific kidney disease models and enhance efforts to identify nephron targeted drugs.
Moreover, the cocktail is powerful enough to reprogram a differentiated type of kidney cell known as a podocyte into an NPC-like state.
Demonstrating the practical applications of their breakthrough, the scientists performed genome editing on the NPCs to screen for genes related to kidney development and disease. This screening identified previously implicated genes, as well as novel candidates.

In a further demonstration, the scientists introduced the genetic mutations responsible for polycystic kidney disease (PKD) into the NPCs. These NPCs developed into mini-kidney structures, known as organoids, exhibiting cysts — the hallmark symptom of PKD. The team then used the organoids to screen for drug-like compounds that inhibited cyst formation.
“This breakthrough has potential for advancing kidney research in many critical ways — from accelerating drug discovery to unraveling the genetic underpinnings of kidney development, disease, and cancer,” said Li. “Importantly, it also provides supplies of NPCs as critical building blocks to build synthetic kidneys for kidney replacement therapy.”
Eighty percent of this work was supported by federal funding from the National Institutes of Health (NIH) (grant numbers DK054364, and T32HD060549) and the NIH Common Fund’s High-Risk High-Reward Research program (grant number DP2DK135739). Additional support came from University Kidney Research Organization (UKRO) foundation funding, a Keck School of Medicine of USC Dean’s Pilot Award, a USC Stem Cell Challenge Grant, a USC Provost’s Undergrad Research Fellowship, a Chan Zuckerberg Initiative seed network grant (CZIF2019-002430), and a CIRM Bridges Award.
McMahon is a scientific advisor or consultant for Novartis, eGENESIS, Trestle Biotherapeutics, GentiBio, and IVIVA Medical. Li, Huang, Zeng, McMahon, Hallows, and Pastor-Soler have applied for intellectual property protection for technologies described in this study.

Loneliness in adulthood follows a U-shaped pattern: it’s higher in younger and older adulthood, and lowest during middle adulthood, reports a new Northwestern Medicine study that examined nine longitudinal studies from around the world.
The study also identified several risk factors for heightened loneliness across the whole lifespan, including social isolation, sex, education and physical impairment.
“What was striking was how consistent the uptick in loneliness is in older adulthood,” said corresponding author Eileen Graham, associate professor of medical social sciences at Northwestern University Feinberg School of Medicine. “There’s a wealth of evidence that loneliness is related to poorer health, so we wanted to better understand who is lonely and why people are becoming lonelier as they age out of midlife so we can hopefully start finding ways to mitigate it.”
Lacking connection can increase the risk for premature death to levels comparable to smoking daily, according to the office of the U.S. Surgeon General, who one year ago called for action to address America’s loneliness epidemic. Graham said her findings underscore the need for targeted interventions to reduce social disparities throughout adulthood to hopefully reduce levels of loneliness, especially among older adults.
Perhaps one day general practitioners could assess levels of loneliness during regular wellness visits to help identify those who might be most at risk, Graham said.
The study will be published April 30 in the journal Psychological Science.
Factors associated with higher persistent loneliness
The study found individuals with higher persistent loneliness were disproportionately women, more isolated, less educated, had lower income, had more functional limitations, were divorced or widowed, were smokers, or had poorer cognitive, physical or mental health.

‘How does loneliness change across the lifespan?’
The study replicated this U-shaped pattern across nine datasets from studies conducted in the U.K., Germany, Sweden, the Netherlands, Australia, Israel and more. Only one of the datasets was from the U.S., which Graham said points to how widespread the loneliness epidemic is globally.
“Our study is unique because it harnessed the power of all these datasets to answer the same question — ‘How does loneliness change across the lifespan, and what factors contribute to becoming more or less lonely over time?’,” she said.
All of the nine longitudinal studies were conducted before the onset of the COVID-19 pandemic, when many researchers found loneliness became even more pronounced.
Why is middle adulthood less lonely?
While this study didn’t specifically examine why middle-aged adults are the least lonely, Graham said it could be because the many demands on a middle-aged person’s life often involve social interactions, such as being married, going to work and making friends with the parents of children’s friends.

But the relationship between social interaction and loneliness is complex. “You can have a lot of social interaction and still be lonely or, alternatively, be relatively isolated and not feel lonely,” Graham said.
As for younger adulthood being a lonelier time, Graham and the study’s co-author Tomiko Yoneda said the study data start right at the end of adolescence, when young adults are often navigating several important life transitions (e.g., education, careers, friend groups, relationship partners and families).
“As people age and develop through young adulthood into midlife, they start to set down roots and become established, solidifying adult friend groups, social networks and life partners,” said Yoneda, assistant professor of psychology at University of California, Davis. “We do have evidence that married people tend to be less lonely, so for older adults who are not married, finding ongoing points of meaningful social contact will likely help mitigate the risk of persistent loneliness.”

A genetic propensity to higher circulating levels of lipids containing arachidonic acid, an omega-6 polyunsaturated fatty acid found in eggs, poultry, and seafood, has been found to be linked with a lower risk for bipolar disorder, according to a new study in Biological Psychiatry, published by Elsevier. This new evidence paves the way for potential lifestyle or dietary interventions.
Bipolar disorder is a debilitating mood disorder characterized by recurring episodes of mania and depression. Although its etiology is still unclear, previous studies have shown that bipolar disease is highly heritable. The findings of this study indicate a link between bipolar disorder and altered metabolite levels, supporting the notion that circulating metabolites play an important etiological role in bipolar disease and other psychiatric disorders.
Lead investigator David Stacey, PhD, Australian Centre for Precision Health, University of South Australia; UniSA Clinical and Health Sciences; and South Australian Health and Medical Research Institute, Adelaide, Australia, explains, “Accumulating evidence indicates a role for metabolites in bipolar disorder and other psychiatric disorders. By identifying metabolites that play causal roles in bipolar disorder, we hoped to be able to highlight potential lifestyle or dietary interventions.”
By applying Mendelian randomization, a powerful causal inference method, the researchers identified 33 out of 913 metabolites studied present in the blood that were associated with bipolar disorder, most of them lipids.
Researchers also found that a bipolar disorder risk gene cluster (FADS1/2/3), which encodes enzymes associated with lipid metabolism, mediated the association between bipolar disorder and the levels of arachidonic acid and other metabolites.
Commenting on the findings, John Krystal, MD, Editor of Biological Psychiatry, says, “Arachidonic acid is typically a widely present omega-6 fatty acid in the body and brain that contributes to the health of cell membranes. This study provides a fascinating step forward in the effort to develop blood biomarkers of bipolar disorder risk, particularly in those patients with bipolar disorder and risk gene variations in the FADS1/2/3 gene cluster.”
Dr. Stacey notes, “Intriguingly, we observed a pattern whereby a genetic propensity to higher levels of lipids containing an arachidonic acid fatty acid side chain was associated with a lower risk of bipolar disorder, while the inverse was true of lipids containing a linoleic acid side chain. Since arachidonic acid is synthesized from linoleic acid in the liver, this suggests arachidonic acid synthesizing pathways are important for bipolar disorder.”
Given its presence in human milk, arachidonic acid is considered essential for infant brain development and is added to infant formula in many countries. Therefore, it may exert an effect on bipolar disorder risk by affecting neurodevelopmental pathways, which would be consistent with contemporary views of bipolar disorder as a neurodevelopmental disorder. Arachidonic acid can be sourced directly from meat and seafood products or synthesized from dietary linoleic acid (e.g., nuts, seeds, and oils).
Dr. Stacey concludes, “To our knowledge, ours is the first study to highlight a potential causal role between arachidonic acid and bipolar disorder. Preclinical studies and randomized controlled trials will be necessary to determine the preventive or therapeutic value of arachidonic acid supplements, perhaps with a particular focus on people with a compromised arachidonic acid synthesizing pathway or with poor natural dietary sources. Our findings also support potential avenues for precision health interventions focused on early life nutrition to ensure that infants and children are receiving enough arachidonic acid and other polyunsaturated fatty acids to support optimal brain development, which may also reduce the risk of bipolar disorder.”