Tag: Academic research

Posted on

Stem Cell Editing Programs the Immune System to Make Own Therapeutic Proteins

For pathogens like HIV, malaria, and rapidly evolving influenza strains, coaxing the immune system to produce the rare, highly potent antibodies needed for protection has long been a scientific bottleneck. Vaccines can train B cells to evolve such broadly neutralizing antibodies, but only under ideal conditions—and only in a small fraction of people. Even attempts to genetically edit mature B cells produced responses that faded as the cells died out.

A team at the Rockefeller University has now taken a more upstream approach: programming hematopoietic stem and progenitor cells (HSPCs)—the source of all B lymphocytes—to carry permanent genetic instructions for therapeutic antibodies or other proteins. Because the immune system naturally amplifies rare, useful cells after vaccination, even a tiny number of edited stem cells can seed a durable, boostable immune response.

“The immune system is inefficient in that it produces a vast quantity of cells to protect itself,” said Harald Hartweger, a research assistant professor in Michel Nussenzweig’s Laboratory of Molecular Immunology. “We wanted to take advantage of the immune system’s ability to amplify useful, rare cells.”

The study, published in Science and titled “B lymphocyte protein factories produced by hematopoietic stem cell gene editing,” demonstrates that CRISPR‑edited HSPCs can mature into B cells that express engineered antibodies upon vaccination. A standard vaccination then acts as the trigger: antigen exposure drives those edited B cells to expand, differentiate into plasma cells, and secrete high titers of the inserted antibody that last long-term.

According to the paper, as few as ~7,000 edited HSPCs were enough to generate “high titers of long‑lasting protective or therapeutic antibodies and/or cargo proteins.” In mice engineered to produce a broadly neutralizing influenza antibody, this response was strong enough to protect against an otherwise lethal viral infection.

The platform proved unexpectedly versatile. Edited B cells could also secrete non‑antibody proteins, pointing to potential applications in genetic diseases. And by mixing HSPCs engineered with different antibody instructions, the researchers created immune systems capable of producing multiple antibodies simultaneously, an approach that could limit viral escape in HIV or other rapidly mutating pathogens. Human HSPCs edited using the same strategy produced functional human B cells in an immunodeficient mouse model, offering an early sign of translational feasibility.

“Our goal is to permanently impact the genome with a single injection, so that the body can make proteins of interest,” Hartweger said. “That protein could be an antibody that’s universally protective against HIV or influenza, but it could also be any therapeutic protein.”

The team is now moving toward preclinical testing in non‑human primates to evaluate protection against HIV and exploring whether similar strategies could be applied to T cells. The broader vision is a generalizable, long‑term protein‑production platform, one that could support treatments for infectious disease, protein deficiencies, autoimmunity, metabolic disorders, and cancer, according to Hartweger.

As Nussenzweig puts it, “The present study proposes a workaround for the antibody problem—a way of getting around the possibility that we may never get to a universal HIV vaccine, while still providing a promising, long‑lasting solution.”

The post Stem Cell Editing Programs the Immune System to Make Own Therapeutic Proteins appeared first on GEN – Genetic Engineering and Biotechnology News.

Posted on

A pancreatic cancer breakthrough, and new hope for an off-the-shelf CAR-T treatment

On this week’s episode of the Readout LOUD: a pancreatic cancer breakthrough and new hope for an off-the-shelf CAR-T treatment in lymphoma. 

Your favorite biotech podcasting crew is back to full strength this week, and we’re bringing you two newsy guest interviews. First, we’ll talk with Allogene Therapeutics Chief Medical Officer Zach Roberts about new study results that bolster the company’s efforts to develop an off-the-shelf CAR-T therapy for B-cell lymphoma, a type of blood cancer.

Read the rest…

Posted on

Intercellular Communication via Condensate Corona-Nanoparticle Complexes

Cells and tissues have a multitude of methods for intercellular communication. Nanoscale assemblies that transfer proteins and RNAs between cells are known, but the impacts of external additions or synthetic materials is unclear.

Researchers from the University College of Dublin’s Centre for BioNano Interactions (CBNI) explored detailed changes in nanostructure-biological hybrid complexes as they leave one cell and enter another.

“We had long believed that there are natural couriers and gateways that allow special, very small particulates to communicate in organisms,” said lead author Kenneth Dawson, DPhil, CBNI director.

The team published their work in a paper titled, “Condensate corona–nanoparticle complexes transfer functional biomolecules between cells” in Nature Materials.

In rare instances, a subset of nanoparticles that enter a cell undergo an unexpected transformation, acquiring a coating known as a “condensate corona.” This corona allows for regulated entrance into the cell.

“By gaining access to these natural gateways, it could be possible to ferry ‘toolkits’ of functional biomolecules, for example, extended corrective messages, directly into previously inaccessible areas within cells, and across biological barriers, greatly improving the effectiveness and, importantly, the safety of RNA-, gene- and protein-based therapies,” said lead author associate professor Yan Yan, PhD, UCD School of Biomolecular and Biomedical Science.

Using “magnetic-cored, silica-shelled nanoparticles precoated with a grafted or adsorbed biomolecular corona,” the researchers created a scaffold that provided the cell with a recognition cue, allowing for the cells to deposit a secondary corona. With magnetic cores, and silica shells that carry fluorescent labels, the nanoparticles are easily controlled, extracted, and visualized.

Live-cell imaging showed that these additionally transformed nanoparticles were re-exported and retained both their original corona, along with their new cell-derived layer.

“By combining magnetic core extraction with an optimized pulse–chase regime and post-isolation washing, we obtained highly reproducible particle-complex isolates with minimal background contamination,” the authors wrote. Analysis showed that the cell-derived corona was “solid-like, structurally stable and biochemically robust.”

They also identified protein profiles using stable-isotope amino acid labelling (SILAC) in the cells producing the corona, followed by mass spec analysis. These proteins have a high affinity for the ER and mitochondria and about 70% of the proteins have been previously associated with mesoscopic intracellular RNA granules.

“With the prototype in our hands, we were able to break into these communications and understand how biological information is shared between cells. From there, we began to send our own messages via the same system,” Dawson noted.

In further tests, the team found that within endosomes of the recipient cell, the corona detaches from the core and the fates of the core and corona diverge, with the proteins and RNA components of the corona escaping the endosome—and escaping degradation—to be distributed within and access targets in the cell. They were able to disrupt this process and keep the corona and the attached materials, in the endosome by grafting short peptides onto the coronal surface.

Utilizing CRISPR-Cas9 they tested the functionality of corona-bound particles that escape the endosome. They generated particle complexes for bioluminescent markers to monitor functionality. Analysis revealed “intact enzymatic activity can be delivered to recipient cells by condensate-borne cargo.”

The authors explained that together, their data suggest these condensates function as an encoded biomolecular transfer program that are activated by the recipient cell. They wrote: “It is remarkable that such architectures, built entirely from endogenous biomolecules of producer cells, can embody transfer programs that overcome most of the challenges faced within nanoscale therapeutics.”

“The findings provide a new blueprint for sending strategic and therapeutically effective biological messages to currently inaccessible locations in the body. That points towards a new concept of medicine that could reverse, rather than manage, currently intractable diseases,” concluded Dawson.

The post Intercellular Communication via Condensate Corona-Nanoparticle Complexes appeared first on GEN – Genetic Engineering and Biotechnology News.

Posted on

Brain Circuits Underlying Placebo Pain Relief Identified in Mice

Though the placebo effect is a well documented phenomenon, the neurological mechanisms that underlie the process are still not fully understood. Now scientists from multiple institutions led by a team at the University of California San Diego (UCSD) have pinpointed the brain circuitry in mice that they believe is responsible for placebo pain relief. Details of their findings are published in a new paper in the journal Neuron. In it, they describe brain regions that support placebo effects and highlight sites where endogenous opioid neuropeptides send signals that are important for placebo pain relief. 

The paper is titled “Top-down control of the descending pain modulatory system drives multimodal placebo analgesia.” According to the team, theirs is the first study to establish placebo mechanisms by adapting a protocol used for humans to work in mice. Working alongside labs at the University of Pennsylvania, University of California Irvine, and elsewhere, the UCSD team detected activity in parts of the mouse brain that correspond to those previously implicated in human studies. Furthermore, by precisely mapping neural pathways and brain activity in the mice, the team identified essential roles for neural circuits that link the cortex to the brainstem and spinal cord during placebo pain relief. 

They also found that training mice to exhibit a placebo effect with one type of pain results in relief from several different types of pain including pain from injuries. That is particularly notable because it has “direct implications for how placebo training in humans might be used to produce resilience to future pain that results from injury,” explained Matthew Banghart, PhD, an associate professor in UCSD’s neurobiology department and lead author on the study. The findings also open a door to “expectancy-driven” placebo effects as a substitute for addictive painkillers, he noted, meaning that it might be possible to use placebo conditioning to train patients to build preemptive resilience to pain.

Full details of the findings and methods used are provided in the paper. In it, the teams explain that they used sensor technology and a light-activated drug developed in the Banghart lab to study the role of naturally-occurring opioid peptides in the brain. Specifically, they used the sensors to detect opioid peptide signaling in the ventrolateral periaqueductal gray (vlPAG) region, a known hub for pain signaling, during placebo trials. They then used the light-activated drug called photoactivatable naloxone, or PhNX, to establish that these opioid peptides actually drive pain relief in a manner similar to drugs like morphine. The light allowed the scientists control and timing of the opioid signaling interference. Using PhNX, they confirmed that both morphine-induced pain relief and placebo pain relief use the same opioid signaling pathway in the vlPAG region of the brain. 

Essentially, “we trained a mouse brain to create its own broad-spectrum painkillers on demand, precisely where they are needed to treat pain, without the off-target effects of opioid-based painkillers,” said Janie Chang-Weinberg, a PhD student in the biological sciences graduate program at UCSD and one of the first authors on the study. 

Future studies planned by the team will dig more deeply into how placebo learning unfolds in the brain and evaluate different placebo training strategies in mice with an eye towards developing protocols that readily translate to produce placebo pain resilience in people living with chronic pain.

The post Brain Circuits Underlying Placebo Pain Relief Identified in Mice appeared first on GEN – Genetic Engineering and Biotechnology News.

Posted on

Proteins.1 Launches to Develop Single Molecule Protein Amplification Tech for Diagnostics

Finnish deep-tech startup, Proteins.1, launched with €4.7 million in pre-seed funding, led by Lifeline Ventures and Cloudberry Ventures, with in-kind support from VTT and Business Finland. Harnessing technology transferred from VTT Technical Research Centre of Finland, Proteins.1 is developing a PCR-like enzyme-free, ultra-sensitive amplification platform for the detection of proteins at the single-molecule level. The firm says it aims to transform early disease diagnostics by enabling detection of disease-related molecular warning signals long before there are clinical signs.

While polymerase chain reaction (PCR) technology has transformed modern diagnostics by allowing tiny amounts of DNA to be amplified into detectable signals, no equivalent amplification method has existed for proteins, which often signal the earliest onset of cancer, neurodegeneration, cardiovascular disease, and inflammatory conditions, the company notes. Proteins.1 aims to leverage its technology to establish a new category of ultra-sensitive protein diagnostics, combining high multiplexing, scalable chip-based detection, and significantly lower capital costs compared to existing systems.

The patented, physics-based technology introduces cyclic signal amplification for proteins, potentially enabling up to 1,000 times better sensitivity than current gold-standard platforms, Proteins.1 claims. Unlike conventional immunoassays that rely on enzymatic reactions prone to variability and noise, the Proteins.1 approach is solid-state, enzyme-free, and compatible with semiconductor-based photonic detection.

The platform replaces enzymatic signal amplification with a physics-based magnetic cycling mechanism that repeatedly reads a single captured protein molecule, accumulating signal clarity without increasing background noise. The company says this supports ultra-high sensitivity combined with high multiplexing, potentially enabling the simultaneous measurement of hundreds of biomarkers from a few drops of blood.

“For decades, diagnostics has been limited not by biology, but by what our instruments can detect,” commented Proteins.1 co-founder and CEO Prateek Singh, who is inventor of the core technology. “The body produces early warning signals long before disease becomes visible. Our mission is to make those signals measurable and actionable, years earlier than today.”

Built on research conducted at VTT and further validated through European Union breakthrough innovation funding, the technology has been granted U.S. and Finnish patents, and additional international applications are pending. Initially, the company aims to develop research-use-only applications in oncology, neurology, and immunology, before progressing toward regulated clinical diagnostics. “Early detection dramatically improves survival rates in diseases such as cancer and neurodegenerative disorders,” Singh continued. “If we can detect disease at the molecular stage rather than the symptomatic stage, we entirely change treatment possibilities.”

Proteins.1 plans to expand its engineering and product development team in Finland during 2026–2027, positioning itself as a European hub for next-generation diagnostic technology. “Proteins.1 represents the kind of deep scientific breakthrough that can redefine an entire industry,” said Jyri Engeström at Lifeline Ventures. “The team combines world-class research with proven experience in building and scaling regulated medtech businesses.” Cloudberry Ventures further highlighted the company’s strong alignment with European strengths in photonics, microfabrication, and precision engineering.

Added Rene Kromhof, at Cloudberry VC, “What sets Proteins.1 apart is a fundamentally new sensing approach. Rather than using enzymes that give you one chance to detect a protein, they use light and thin-film transistors to amplify the signal from a single protein until it rises above the noise. That dramatically improves sensitivity, and ultimately, how early disease can be caught.”

CEO Prateek Singh has previously raised venture capital for microfluidics ventures and holds multiple patent families. Co-founder and COO Harri Hallila previously built and exited a regulated medical device company. The broader team includes commercial leadership with experience in leading diagnostics platforms.

The post Proteins.1 Launches to Develop Single Molecule Protein Amplification Tech for Diagnostics appeared first on GEN – Genetic Engineering and Biotechnology News.

Posted on

Artificial Intelligence Design for Race-Based Prostate Cancer Stage Classification With Multilayer Perceptron: Feature Selection Optimization Approach

Background: Prostate cancer progression exhibits significant variability influenced by biological and racial factors. DNA methylation profiling has shown potential in early cancer detection, but its integration with machine learning across racially diverse populations remains limited. Objective: This study aimed to develop a prostate cancer stage classifier for the majority White cohort using DNA methylation data and a multilayer perceptron (MLP) model in order to classify prostate cancer stages into early (stages I-II) and late (stages III-IV) stages and assess its performance when applied to other racial groups to highlight the need for race-specific models. Methods: Methylation and phenotype data from the TCGA-PRAD (The Cancer Genome Atlas Prostate Adenocarcinoma) dataset were processed using differentially methylated position (DMP) analysis to identify CpG sites correlated with cancer stages. These features were further refined through recursive feature elimination (RFE) and used to train MLP models. Shapley Additive Explanations (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) were used to interpret the model and identify key DNA methylation features contributing to model predictions. Results: The best-performing model achieved 95% accuracy and up to 99% area under the curve on the majority race (White) training data using 90 selected features. However, performance declined sharply in racial minority groups, revealing the effects of sample imbalance and race-specific methylation patterns. Feature importance examination indicated strong patterns within certain CpG sites driving model predictions. Conclusions: We propose a race-aware MLP model for prostate cancer stage classification using DNA methylation data, which has been optimized through DMP and RFE-based feature selection. SHAP and LIME confirmed the predictive relevance of selected CpG sites, supporting model transparency. The results highlight high performance within the White cohort but reveal poor generalization to racial minority groups, emphasizing the importance of race-specific modeling strategies.
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/1f1194b827c613bf0fab0334ac95145e" />

Posted on

A Digital Inclusion Intervention to Improve Access to a Digital Health Intervention Among Digitally Excluded Adults: Mixed Methods Pilot Randomized Controlled Trial

Background: The National Health Service 10-year health plan emphasizes an increasing shift toward digital health care delivery. However, there is limited research on how best to support, engage, and include individuals who are digitally excluded. As health care services become more digitally driven, evidence-based interventions are needed to address digital exclusion and ensure equitable access to care, particularly for people living with long-term conditions. Objective: This study aimed to evaluate the feasibility and acceptability of providing digital literacy training alongside a digital health intervention (DHI; Ex-Tab intervention), compared with providing a DHI alone. Kidney Beam, a DHI designed to promote physical activity and improve quality of life in people with chronic kidney disease (CKD), was used as an exemplar DHI. Methods: This mixed methods, single-site pilot randomized controlled trial recruited 40 adults with CKD who were digitally excluded. Digital exclusion was defined as lacking access to a Wi-Fi–enabled digital device or having a Digital Health Care Literacy Scale (DHLS) score of <7 (range 0‐21). Participants were randomized 1:1 to receive either the Kidney Beam Ex-Tab intervention or Kidney Beam alone (control). The intervention group received a Wi-Fi–enabled iPad on loan with Kidney Beam preinstalled, digital literacy training, and ongoing support to access the 12-week Kidney Beam program (twice weekly live exercise and education sessions). The control group received sign-up instructions for Kidney Beam only. Feasibility outcomes were assessed against a priori progression criteria and included screening, recruitment, retention, adherence, safety, and acceptability. Secondary outcomes included the Kidney Disease Quality of Life Questionnaire, Chalder Fatigue Questionnaire, and Patient Health Questionnaire-4. Outcomes were measured at baseline and 12 weeks. Acceptability and user experience were explored through semistructured interviews with participants from both groups at 12 weeks (n=25). Results: Between September 2023 and September 2024, a total of 169 individuals were screened and 40 were enrolled (median age 66.5 years; 20 male individuals; median DHLS score: 4). Twenty-one participants were randomized to the Kidney Beam Ex-Tab group and 19 to the Kidney Beam alone group. Of the 40 participants, 35 (88%) completed the 12-week follow-up (intervention: n=18; control: n=17). All prespecified feasibility criteria for recruitment, retention, adherence, and safety were met. Qualitative findings indicated that the tablet loan and digital literacy training were acceptable and highly valued, enhancing confidence, motivation, and DHI engagement. Providing loaned devices was particularly important for overcoming access barriers, especially for participants unable to afford their own device. Conclusions: Providing Wi-Fi–enabled devices and digital literacy training alongside a DHI was feasible and acceptable for people with lower digital literacy levels. The findings support progression to a future definitive multicenter trial or implementation study and offer transferable insights for the design of digital inclusion strategies for other long-term health conditions. Trial Registration: ClinicalTrials.gov NCT04872933; https://clinicaltrials.gov/study/NCT04872933
Posted on

Feasibility and Acceptability of an eHealth-Based Physical Activity Coaching Intervention During Pulmonary Rehabilitation for People With Chronic Obstructive Pulmonary Disease: Mixed Methods Study

Background: Physical inactivity is a modifiable and significant trait in people with chronic obstructive pulmonary disease (COPD). While traditional exercise-based pulmonary rehabilitation (PR) improves symptoms and exercise tolerance, its impact on physical activity (PA) levels remains limited. Digital health (eHealth) interventions may help address this gap. Objective: This study aimed to assess the feasibility and acceptability of integrating an eHealth PA coaching intervention into PR for people with COPD. Methods: Patients enrolled in an outpatient PR program were recruited for a 3-week PA coaching intervention, which used a smart band connected to a mobile patient app and a web application for health care professionals (HCPs). The intervention included PA monitoring (steps per day); weekly goal setting; and app notifications for goal updates, achievement, and motivational messages. Weekly telephone calls supported goal adjustment and identification of PA barriers. The acceptability of the intervention was explored through a patient focus group. Results: Five patients with COPD (mean 67, SD 9 years; n=4, 80% female; mean predicted forced expiratory volume at 1 second of 49%, SD 23%) participated with 100% retention and adherence to the intervention (daily synchronization). No adverse events or PA barriers were identified. One patient reported an app connection issue that was resolved by restarting the app. Patients found the app easy to use and helpful for their PA awareness and remote monitoring by HCPs. Weekly goal adjustments and contact with an HCP were valued. Limitations regarding the app use included a lack of personalization, goal setting restricted to steps, and occasional step miscounts. Conclusions: The intervention was feasible and well accepted. Future studies with a larger sample are needed to assess the impact of the intervention on PA outcomes.
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/952c30728d3fa52aeadf773bab87548a" />

Posted on

Advances in Stem Cell‑Derived Insulin‑Producing Cells for Type 1 Diabetes

Researchers at Karolinska Institutet and KTH Royal Institute of Technology have developed an improved method for creating insulin-producing cells from human stem cells. In a newly published study, the team demonstrated that these cells effectively regulate blood sugar levels in laboratory tests and can reverse diabetes in mice.

“We have developed a method that reliably produces high-quality insulin-producing cells from multiple human stem cell lines,” said Per-Olof Berggren, PhD, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet. “This opens up opportunities for future patient-specific cell therapies, which could reduce immune rejection.” Berggren and Siqin Wu, PhD, researcher at Spiber Technologies AB (formerly at Karolinska Institutet), are co-corresponding authors of the researchers’ published paper in Stem Cell Reports, titled “An optimized protocol for efficient derivation of pancreatic islets from multiple human pluripotent stem cell lines.”

Type 1 diabetes (T1D) occurs when the immune system destroys insulin-producing cells in the pancreas, meaning the body can no longer absorb glucose from the blood and regulate blood sugar levels. “In type 1 diabetes (T1D), autoimmune destruction of β cells results in loss of glycemic control,” the authors wrote.

One possible treatment strategy is to replace these cells with new ones. However, previous methods of producing such cells from stem cells have often yielded mixed results. Stem cell therapy for type 1 diabetes is already being tested in several clinical trials. However, a challenge with previous methods is that the stem cells often develop into a combination of the desired and undesired cell types, increasing the risk of complications. Another challenge is that the insulin-producing cells created are often not mature enough to respond well to glucose.

“The success of cell therapy for type 1 diabetes (T1D) depends on reliable differentiation of stem cells into functional pancreatic islets,” the authors noted. They pointed out that previous protocols have exhibited variable efficiency across different human pluripotent stem cell (hPSC) lines. “Differentiation beyond the stage (S) 4 pancreatic progenitor (PP) stage frequently yields heterogeneous cultures containing proliferative non-endocrine cells and immature endocrine cells … increasing the risk of cyst or tumor formation,” the team further commented.

The newly optimized production process reported by Berggren and colleagues yields more mature and purer insulin-producing cells than previous methods. In a laboratory setting, the cells were able to secrete insulin and responded strongly to glucose. When the researchers transplanted these cells into streptozotocin (STZ)-induced diabetic mice, the animals gradually regained the ability to regulate their blood sugar. “By adjusting the culture steps and allowing the cells to form three-dimensional clusters themselves, many unwanted cell types are eliminated and the cells gain a better ability to respond to glucose, according to the researchers. “Single-cell analyses show that the SC-islets are free of non-endocrine cell populations before and after transplantation,” the team stated.

The transplantation was performed in the anterior chamber of the eye (ACE) which provides a transparent and accessible site for noninvasive monitoring of engrafted SC-islets through the cornea, the team pointed out. Transplantation into this compartment is also straightforward and minimally invasive.  In their paper, the team noted, “Intraperitoneal glucose tolerance tests (IPGTT) at three, four, and six months post-transplantation showed improved glucose handling over time … SC-islet transplantation reversed hyperglycemia by three months, and by five–six months blood glucose levels fell slightly below pre-STZ baselines.”

Berggren commented, “This is a technique we use to monitor the development and function of the cells over time in a minimally invasive way. We observed that the cells gradually matured after transplantation, retaining their ability to regulate blood sugar for several months, which demonstrates their potential for future treatments.”

Fredrik Lanner, PhD, professor at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and last author of the paper, added, “This could solve several of the problems that have previously hindered the development of stem cell-based treatments for type 1 diabetes. Building on this, we will work towards clinical translation aiming at treating type 1 diabetes.” In their report the authors concluded, “Our protocol generated glucose-responsive SC-islets from all eight hPSC lines tested … demonstrating potential for autologous applications … Our efficient differentiation protocol represents a key step toward autologous cell therapy, though further work is required to realize this goal.”

The post Advances in Stem Cell‑Derived Insulin‑Producing Cells for Type 1 Diabetes appeared first on GEN – Genetic Engineering and Biotechnology News.

Posted on

Aging Immune Cells Linked to Fatty Liver Disease 

UCLA researchers have found that macrophages with a senescent phenotype may be actively driving progression of fatty liver disease. A study published today in Nature Aging reports that clearing this aging cell population in mice dramatically reduced liver inflammation and reversed damage even without any dietary changes. 

“Senescent cells are fairly rare, but think of them like a broken-down car,” said Anthony J. Covarrubias, PhD, assistant professor at the UCLA David Geffen School of Medicine and senior author of the study. “Just one stalled car can back up traffic for miles. Now imagine five or ten of them slowly accumulating. That’s what these cells do to a tissue: even a small number causes enormous disruption.”

As cells age and become senescent, they are known to drive chronic inflammation across a range of tissues. While previous research has shown that eliminating senescent cells can improve health and lengthen lifespan, there is still a limited understanding of which cells undergo the senescence process and how to distinguish them from healthy cells.

This is especially the case for cells that naturally share hallmark features with senescent cells, as is the case of macrophages; when activated, macrophages secrete a range of inflammatory cytokines and immunomodulatory metabolites that many senescent cells also produce when driving chronic, age-driven inflammation. 

The researchers found that no single biomarker was enough to identify senescent macrophages. Instead, they identified that this aging cell population was defined by the simultaneous expression of p21 and Trem2 proteins, together with altered nuclear morphology, lipid metabolism and type I interferon (IFN) hyperactivation.

In mice, senescent macrophages carrying this molecular signature were found to surge from 5% in young mice to up to 80% in older ones, correlating with a rise in chronic liver inflammation during normal aging. In addition, excess cholesterol was found to push macrophages into a senescent state where they stopped dividing, increased secretion of inflammatory proteins and activated expression of p21 and Trem2. 

“Physiologically, macrophages can handle cholesterol metabolism,” said Ivan A. Salladay-Perez, graduate student in the Covarrubias lab and lead author of the study. “But in a chronic state, it’s pathological. When you look at fatty liver disease, which is driven by overnutrition and too much cholesterol in the blood, that excess cholesterol appears to be a major driver of the senescent macrophage population.”

Experiments using a publicly available genomic dataset of patient liver biopsies found that the same senescent macrophage signature was increased in diseased livers compared to healthy ones, suggesting they also play a role in chronic liver disease in humans. 

In mice with a high-fat, high-cholesterol diet, a drug that selectively kills senescent cells was found to reduce overall body weight and make livers healthier—smaller and with a lower fat percentage. These findings suggest that clearing senescent macrophages from the liver does not just slow the progression of fatty liver disease, but can actually reverse it without changing the diet. 

Because the drug tested in mice is too toxic for humans, the researchers plan to begin drug screening studies to identify new compounds that can replicate these effects. They will also be exploring whether this therapeutic target could be expanded to a range of other age- and cholesterol-driven conditions where senescent macrophages have been observed.

“It all goes back to understanding how these cells arise in the first place,” said Salladay-Perez. “If you really understand the basic mechanisms driving inflammation with aging, you can target those same mechanisms to treat not just fatty liver disease, but atherosclerosis, Alzheimer’s and cancer.” 

The post Aging Immune Cells Linked to Fatty Liver Disease  appeared first on Inside Precision Medicine.