BUFFALO, NY - June 4, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 20, 2025, titled “Targeting PCNA/AR interaction inhibits AR-mediated signaling in castration resistant prostate cancer cells."

In this study, authors Shan Lu and Zhongyun Dong from the University of Cincinnati College of Medicine investigated how interfering with a protein interaction could reduce prostate cancer growth. Their study based on prostate cancer cells shows that blocking the link between PCNA, a protein important for DNA repair, and the androgen receptor (AR), which drives prostate cancer growth, can slow down cancer cell multiplication. This discovery could lead to a new treatment for patients with advanced prostate cancer, particularly those no longer responding to hormone therapy.

Prostate cancer is one of the most common cancers in men. Many patients eventually become resistant to hormone treatment. In this advanced stage, called castration-resistant prostate cancer (CRPC), tumors continue to grow by using either the full-length androgen receptor (AR-FL) or altered versions called AR variants (AR-Vs). This study shows that the interaction between AR and PCNA helps both AR-FL and AR-Vs remain active, supporting cancer cell survival and growth.

The researchers identified a new region in the AR that binds to PCNA. They developed a small peptide, R9-AR-PIP, to mimic this region and block the AR-PCNA connection. They found that this peptide reduced AR’s ability to bind DNA and lowered the levels of key genes involved in cancer cell growth. Importantly, the peptide was effective against both types of AR, including the variant forms that are especially challenging in CRPC.

“We identified a second PIP-box (PIP-box592) in the DNA binding domain of AR and found that dihydrotestosterone enhances the binding of full-length AR (AR-FL) but not a constitutively active variant (AR-V7) to PCNA.”

They also tested a small molecule, PCNA-I1S, which interferes with PCNA’s ability to move to the cell nucleus and interact with AR. This molecule showed similar effects as the peptide, reducing AR activity and stopping cancer cell growth. Together, these findings suggest that targeting PCNA/AR interactions could be a promising strategy to fight CRPC, especially in patients with limited treatment options.

One key result was that both the peptide and the small molecule reduced the levels of cyclin A2, a protein that helps cells divide and is often overexpressed in CRPC. Since this protein is linked to patients' poor outcomes, its reduction could be especially beneficial.

This study improves our understanding of how prostate cancer continues to grow even after hormone treatments fail. By blocking a crucial helper of the androgen receptor, researchers have uncovered a new way to potentially slow or stop the disease. Further studies in animal models are needed, but this approach could lead to more effective treatments for men with advanced prostate cancer.

DOI - https://doi.org/10.18632/oncotarget.28722

Correspondence to - Zhongyun Dong - dongzu@ucmail.uc.edu

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Keywords - cancer, PCNA, androgen receptor, PCNA inhibitors, AR splicing variants, CRPC

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Oncotarget

Targeting PCNA-Androgen Receptor Interaction Suppresses Prostate Cancer Cell Growth

The James is a leader in an advanced surgical technique that delivers heated chemotherapy directly to the cancerous cells in patients with rare and advanced types of cancers in the abdomen. “The heat helps the effect of the chemotherapy when it comes into contact with the cancer cells,” said Dr. Pamela Lu, a surgical oncologist and the lead of the James Hyperthermic Intraperitoneal Chemotherapy (HIPEC) team. “And the heat alone can have a toxic effect in killing cancer cells.” The HIPEC surgery is used for patients with cancer in the abdomen and peritoneal lining of the abdomen. “The cancer can look like tiny white spots, it can be raised or flat” and it can be located in several different areas, Lu said. The first step of the HIPEC procedure is to explore the abdomen and peritoneal lining “and take a survey of how much cancer is there,” Lu said. A scoring system is used to determine how much cancer is in several different regions, “how much surgery a patient will need” and if the initial cytoreduction surgery can be effective to remove all visible tumors. “Once this is complete, we proceed with HIPEC, through a hot chemotherapy bath that enters the site through tubes and a special profusion machine that allows the chemo solution to circulate through the abdomen.” The HIPEC technique leads to better outcomes because the direct access to any remaining cancer cells after surgery allows Lu “to give higher doses of chemotherapy with reduced toxicity.”

Episode 195: The High-Tech HIPEC Surgery for Advanced Abdominal Cancers, with Dr. Pamela Lu

BUFFALO, NY — September 2, 2025 — A new #research paper featured on the #cover of Volume 17, Issue 8 of Aging (Aging-US) was #published on July 30, 2025, titled “Exosomes released from senescent cells and circulatory exosomes isolated from human plasma reveal aging-associated proteomic and lipid signatures.”

In this study, led by first authors Sandip Kumar Patel and Joanna Bons, along with corresponding author Birgit Schilling from The Buck Institute for Research on Aging, researchers found that exosomes—tiny particles released by cells—carry molecular signatures that indicate both biological aging and cellular senescence. These signatures include proteins, lipids, and microRNAs associated with inflammation, oxidative stress, and tissue remodeling. The findings could enhance our understanding of biological aging and help in developing future anti-aging therapies.

Senescence is a state in which cells stop dividing but remain metabolically active. These cells often release harmful substances, known collectively as the senescence-associated secretory phenotype (SASP), that can affect nearby tissues. This study shows that exosomes are an important component of this secretory profile.

The researchers analyzed exosomes from senescent human lung cells and from the blood plasma of both young and older adults. They identified over 1,300 proteins and 247 lipids within these particles. Many of these molecules were significantly altered with age.

“In parallel, a small human plasma cohort from young (20–26 years) and old (65–74 years) individuals revealed 1,350 exosome proteins and 171 plasma exosome proteins were altered in old individuals.”

Exosomes from older individuals contained more inflammation-related proteins and fewer antioxidants, while those from senescent cells showed lipid changes associated with membrane integrity and cellular stress. These changes suggest that exosomes may play a role in spreading senescence to nearby cells, a process known as secondary senescence.

The study also identified distinct patterns in microRNAs—small molecules that regulate gene expression—found in the blood of older adults. Some of these, including miR-27a and miR-874, have previously been associated with cognitive decline and chronic illnesses, highlighting their potential as biomarkers for biological aging.

Although the study involved a limited number of samples, it provides strong early evidence that exosomes reflect the molecular changes associated with aging. By showing how these particles carry and possibly spread aging-related signals throughout the body, the research opens new possibilities for diagnosing and treating age-related diseases.

DOI - https://doi.org/10.18632/aging.206292

Corresponding author - Birgit Schilling – bschilling@buckinstitute.org

Video short - https://www.youtube.com/watch?v=tcyAZahw-g8

Keywords - aging, proteomics, senescence, exosomes, data-independent acquisitions

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Aging (Aging-US)

New Study Links Exosomes to Biological Aging

BUFFALO, NY — September 4, 2025 — A new #research perspective was #published  in Volume 17, Issue 8 of Aging (Aging-US) on August 16, 2025, titled “Age-related diseases as a testbed for anti-aging therapeutics: the case of idiopathic pulmonary fibrosis.”

In this research perspective, Alex Zhavoronkov, Dominika Wilczok, Feng Ren, and Fedor Galkin, from Insilico Medicine, Buck Institute for Research on Aging, and Duke University, propose a new method to evaluate age-related diseases based on how closely they align with the biological processes of aging. Their analysis shows that idiopathic pulmonary fibrosis (IPF), a progressive lung condition, is one of the diseases most strongly associated with aging. This makes IPF a promising model for testing new anti-aging therapies with the potential to treat multiple age-related conditions.

“This perspective explores how aging-related diseases (ARDs) can serve as experimental platforms for discovering new geroprotective interventions.”

While many age-related diseases are used as models for aging research, not all accurately reflect the biology of aging. To address this, the authors developed a scoring system that measures how closely a disease is connected to the key hallmarks of aging, such as inflammation, genetic instability, and impaired cellular repair. Using this system, they evaluated 13 common age-related diseases and found that IPF had a particularly high overlap with aging biology.

IPF is a chronic disease that causes scarring in the lungs and a rapid decline in lung function. In contrast to the gradual loss of function seen in normal aging, IPF progresses more than five times faster. The authors highlight that IPF shares nearly all of the biological features associated with aging. These similarities make IPF a strong candidate for studying aging and testing therapies that target its underlying causes.

The authors also discuss different therapies currently being developed for IPF that are also designed to address aging itself. These include drugs that clear senescent cells, activate telomerase to maintain chromosome health, or repair damaged signaling between cells. Some of these treatments, such as senolytic combinations and AI-discovered compounds like rentosertib, are already showing early promise in preclinical or clinical trials.

In addition, the authors point out that IPF’s fast progression and clearly measurable outcomes offer an advantage for clinical testing. If a therapy proves effective in IPF, it may also be useful for other conditions that share similar aging-related mechanisms, including diabetes, arthritis, and heart disease. This approach could accelerate drug development and reduce costs by focusing on therapies that target shared biological pathways.

Overall, this perspective supports a shift in pharmaceutical research toward treating aging as an underlying cause of many chronic diseases. By positioning IPF as a model for aging-related drug development, the authors propose a strategic pathway for testing and expanding anti-aging therapies across a wide range of health conditions.

DOI - https://doi.org/10.18632/aging.206301

Corresponding author - Alex Zhavoronkov – alex@insilico.com

Video short - https://www.youtube.com/watch?v=p5ur7itzvSI

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Idiopathic Pulmonary Fibrosis Identified as a Model for Anti-Aging Drug Development

As the global population grows older, understanding what drives the aging process is becoming increasingly important. Diseases like Alzheimer’s, cardiovascular conditions, and cancer are more common with age, yet many current treatments only manage symptoms rather than addressing the underlying biological causes.

One contributor to aging is the buildup of “senescent” cells—cells that have stopped dividing but do not die. These cells can harm nearby tissues by releasing molecular signals, a process known as secondary senescence.

Scientists have found that senescent cells release tiny particles called exosomes. A research team from The Buck Institute for Research on Aging recently discovered that these exosomes carry aging-related messages through the bloodstream. Their study, titled “Exosomes released from senescent cells and circulatory exosomes isolated from human plasma reveal aging-associated proteomic and lipid signatures,” was featured as the cover article in Aging (Aging-US), Volume 17, Issue 8.

Full blog - https://aging-us.org/2025/09/how-exosomes-spread-aging-signals-and-could-support-anti-aging-research/

Paper DOI - https://doi.org/10.18632/aging.206292

Corresponding author - Birgit Schilling - bschilling@buckinstitute.org

Video short - https://www.youtube.com/watch?v=tcyAZahw-g8

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Keywords - aging, proteomics, senescence, exosomes, data-independent acquisitions

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How Exosomes Spread Aging Signals and Could Support Anti-Aging Research

This special episode of the Heartwood Podcast explores the brotherhood created among members of The Easley Branch record label and their artistic expression. RaShad Eas, B God Body, and JS2000 discuss their use of music to overcome challenges and enhance their experience in university and professional settings. The members also speak to the equanimity they exude and the importance of their desire for more knowledge. Tune in and don’t miss out on this wisdom. 

They are joined by DJ Green as he films. 


The Branch Interview

in this episode, Irish theologian, storyteller, poet, conflict mediator, and host of the podcast Poetry Unbound Pádraig Ó Tuama speaks of the thrilling notion that “all language can do the work of delight or terror in us.” In this conversation, Leader’s Way hosts talk with Pádraig about  the complex relationship between poetry and prayer, the timeless wisdom of Meister Eckhart, and the delightful tradition of the Irish civil servant poet. Pádraig reads several of his poems throughout this episode and shares some of his own story, including his early call to the priesthood and its rejection by the Catholic Church.

Host: Brandon Nappi with Whitney Coe and Misty Krasawksi
Guest: Pádraig Ó Tuama
Production: Goodchild Media
Instagram: @theleadersway.podcast berkeleydivinity.yale.edu/podcast
You can support our work at https://tinyurl.com/support-transforming-leaders


61: Poetry by Heart with Pádraig Ó Tuama

In this episode, Michelle Snyder, author, therapist, leadership coach, and the executive director of Soul Shop, speaks directly to faith leaders about the importance of talking about and tending to suicide in our communities, and training for the work of suicide prevention. Michelle talks with Brandon, Whitney, and Misty about the moment we are in, in which isolation is growing and suicide is on the rise, but faith communities have something to offer.

*If you or someone you know is experiencing suicidal thoughts or a crisis, please reach out immediately to the National Suicide Prevention Lifeline at 988.

Host: Brandon Nappi with Whitney Coe and Misty Krasawksi
Guest: Michelle Snyder
Production: Goodchild Media
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62: We Have To Talk About Suicide with Michelle Snyder

BUFFALO, NY — September 9, 2025 — A new #research paper was #published in Volume 17, Issue 8 of Aging-US on August 1, 2025, titled “Causal relationships between gut microbiome and hundreds of age-related traits: evidence of a replicable effect on ApoM protein levels.”

In this study, Federica Grosso, Daniela Zanetti, and Serena Sanna from the Institute for Genetic and Biomedical Research (IRGB) of the National Research Council (CNR), Italy, uncovered new associations between gut microbiome and the aging process. The researchers found that certain microbial characteristics may causally influence proteins in the blood linked to inflammation and heart health. These findings could help explain how age-related diseases like cardiovascular conditions and macular degeneration are influenced by changes in the gut ecosystem.

The gut microbiome, the collection of microorganisms living in the digestive system, plays a major role in immune function and metabolic health. As people age, this microbial community shifts, often leading to imbalances associated with inflammation and chronic disease. To explore how these changes might affect the body, the researchers used Mendelian Randomization—a method that leverages genetic data—to test over 55,000 possible causal connections between gut microbial characteristics and age-related health indicators.

The study identified 91 significant causal relationships. Among them, the researchers found that higher levels of certain gut bacteria were associated with increased risk of age-related macular degeneration. Another finding was the association between a metabolic pathway in the gut, called “purine nucleotides degradation II,” and lower levels of apolipoprotein M (ApoM), a protein that helps protect against heart disease. This result was validated using data from an independent study, strengthening the evidence.

“Unlike previous studies, we performed replication analyses for the significant results using independent GWAS datasets, a fundamental step that has often been overlooked.”

The study also revealed how some bacteria may affect protein levels differently depending on a person’s blood type. Specifically, in individuals with blood type A, certain gut microbes that can break down a sugar called GalNAc may influence proteins related to inflammation and cardiovascular health. This suggests that personalized approaches to managing age-related diseases could consider both gut microbiota and genetic factors like blood type.

The research team followed strict guidelines to reduce false findings and confirmed its key results in independent datasets. By carefully testing for reverse causality and other biases, the authors provided strong evidence that the gut microbiome can influence critical aspects of aging biology.

Although more research is needed to fully understand the biological pathways involved, these findings suggest that targeting the gut microbiota might help delay or reduce age-related inflammation and disease. The study lays a foundation for future therapeutic strategies that could include diet, probiotics, or other microbiome-based interventions.

DOI - https://doi.org/10.18632/aging.206293

Corresponding author - Serena Sanna - serena.sanna@cnr.it

Abstract video - https://www.youtube.com/watch?v=CWky6jlHKUs

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Aging-US

Gut Microbiome Influences Proteins That Drive Aging and Disease

BUFFALO, NY — September 11, 2025 — A new #research paper was #published  in Volume 17, Issue 8 of Aging-US on August 8, 2025, titled “AI-driven toolset for IPF and aging research associates lung fibrosis with accelerated aging.”

In this study, researchers Fedor Galkin, Shan Chen, Alex Aliper, Alex Zhavoronkov, and Feng Ren from Insilico Medicine used artificial intelligence (AI) to investigate the similarities between idiopathic pulmonary fibrosis (IPF), a severe lung disease, and the aging process. Their findings show that IPF is not simply accelerated aging, but a distinct biological condition shaped by age-related dysfunction. This insight may lead to a new approach in how scientists and clinicians treat this complex disease.

IPF mainly affects individuals over the age of 60. It causes scarring of lung tissue, making it harder to breathe and often leading to respiratory failure. Current treatments can slow the disease but rarely stop or reverse its progression. The researchers used AI to identify shared biological features between aging and fibrosis, finding new potential targets for therapy.

The team developed a “proteomic aging clock” based on protein data from more than 55,000 participants in the UK Biobank. This AI-driven tool accurately measured biological age and found that patients with severe COVID-19, who are at increased risk for lung fibrosis, also showed signs of accelerated aging. This suggests that fibrosis leaves a detectable biological trace, supporting the use of aging clocks in studying age-related diseases.

“For aging clock training, we used the UK Biobank collection of 55319 proteomic Olink NPX profiles annotated with age and gender.”

They also developed a custom AI model, ipf-P3GPT, to compare gene activity in aging lungs versus those with IPF. Although some genes were active in both, many showed opposite behavior. In fact, more than half of the shared genes had inverse effects. This means IPF does not just speed up aging but also disrupts the body’s normal aging pathways.

The study identified unique molecular signatures that distinguish IPF from normal aging. While both involve inflammation and tissue remodeling, IPF drives more damaging changes to lung structure and repair systems. This difference could guide the development of drugs that specifically target fibrosis without affecting normal aging.

By combining AI with large-scale biological data, the study also introduces a powerful toolset for examining other age-related conditions such as liver and kidney fibrosis. These models may support personalized treatments and expand understanding of the relationships between aging and disease, opening new directions for therapy development.

DOI - https://doi.org/10.18632/aging.206295

Corresponding author - Alex Zhavoronkov - alex@insilico.com

Abstract video - https://www.youtube.com/watch?v=24lX2lHbt7o

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Keywords - aging, IPF, generative AI, transformer, proteomics

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AI Tools Uncover New Link Between Idiopathic Pulmonary Fibrosis and Aging

Immunotherapy is not usually effective against pancreatic cancer (PC), but a new study published in Oncotarget (Volume 16, 2025) highlights rare cases where it did help. These examples, though uncommon, may offer valuable insights for future treatment.

Pancreatic Cancer and Immunotherapy

Pancreatic cancer is often diagnosed at an advanced stage, which limits treatment options and contributes to its poor prognosis. While chemotherapy remains the standard treatment, it usually offers only modest benefits in terms of survival. Immunotherapy—an approach that activates the immune system to fight cancer—has been effective in other cancers but has shown limited success in PC.

This is largely due to the tumor’s ability to suppress immune responses and create an environment that protects it from attack. Currently, these drugs are only approved for a small subset of patients whose tumors have a specific genetic feature called high microsatellite instability (MSI-high), found in just 1 to 2 percent of cases.

The Study: Pancreatic Cancer Immunotherapy Responders

The study, titled “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence,” was led by first author Kavin Sugumar and corresponding author Jordan M. Winter, from University Hospitals Seidman Cancer Center. 

The researchers examined medical records from 14 patients with pancreatic ductal adenocarcinoma (PDAC) who had responded unexpectedly well to immune checkpoint inhibitors—drugs that help reactivate immune cells to attack cancer. The drugs included PD-1 inhibitors such as pembrolizumab and nivolumab, CTLA-4 inhibitors like ipilimumab, and agents targeting tumor-associated macrophages. To find these rare cases, the research team contacted 471 oncologists from 91 major U.S. cancer centers between 2020 and 2021.

Full blog - https://www.oncotarget.org/2025/09/11/immunotherapy-response-in-pancreatic-cancer-what-a-new-study-reveals/

Paper DOI - https://doi.org/10.18632/oncotarget.28739

Correspondence to - Jordan M. Winter - jordan.winter@UHHospitals.org

Abstract video - https://www.youtube.com/watch?v=VeWTcuVmqgM

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Keywords - cancer, pancreatic adenocarcinoma, immunotherapy, exceptional responders, microsatellite instability, survival

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Immunotherapy Response in Pancreatic Cancer: What a New Study Reveals

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form and then quickly released to Pubmed.

Oncotarget is now indexed by MEDLINE, PubMed and PMC/PubMed.

Read about the Oncotarget Scientific Integrity Process: https://www.oncotarget.com/scientific_integrity/

Targeting PCNA-Androgen Receptor Interaction Suppresses Prostate Cancer Cell Growth

Oncotarget Podcast

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