BUFFALO, NY – June 9, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 20, 2025, titled “Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis.”

In this study, led by first author Nawar Al Nasralla and corresponding author Catherine R. Sears, from the Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis and the Richard L. Roudebush Veterans Affairs Medical Center, researchers investigated how cigarette smoke and reduced DNA repair capacity contribute together to the development of lung cancer. They found that when a critical DNA repair protein called XPC is decreased and lung cells are exposed to cigarette smoke, the combination causes extensive damage and significantly increases cancer risk.

Non-small cell lung cancer (NSCLC) develops through both genetic and environmental factors. This study focused on how cigarette smoke affects the body’s natural ability to repair DNA. The researchers studied the role of XPC, a protein essential for recognizing and repairing harmful DNA changes caused by tobacco smoke. They found that low levels of XPC — commonly seen in lung cancer patients — made lung cells less capable of repairing DNA. This made the cells unstable and more likely to become cancerous. These changes were most pronounced in normal lung cells, suggesting that the earliest stages of disease occur before cancer is even detected.

The findings support a “double hit” model, where both cigarette smoke and reduced DNA repair work together to drive cancer development. In laboratory experiments, normal lung cells with low XPC levels showed more damage and cell death after cigarette smoke exposure. By contrast, lung cancer cells were more resistant to smoke damage, even when XPC was low, indicating that critical changes had likely occurred earlier in the disease process.

“Our study suggests that cigarette smoke exposure leads to decreased XPC mRNA expression, exacerbates total and oxidative DNA damage, hinders NER, and may contribute to lung cancer development.”

The study also showed that DNA repair ability declined significantly in healthy cells after smoke exposure, but this effect was not seen in cancer cells. In addition, the researchers confirmed that XPC gene activity was lower in actual lung tumor tissue compared to nearby healthy lung tissue. This pattern was consistent across both adenocarcinoma and squamous cell carcinoma, the two main types of NSCLC.

These results add to our understanding of how lung cancer begins at the molecular level. By showing how cigarette smoke and reduced DNA repair combine to create genetic instability, the research points toward new strategies for prevention. A better understanding of XPC’s role could help identify high-risk individuals and inform future efforts to stop lung cancer before it begins.

DOI - https://doi.org/10.18632/oncotarget.28724

Correspondence to - Catherine R. Sears - crufatto@iu.edu

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Keywords - cancer, DNA repair, DNA damage, lung adenocarcinoma, squamous cell carcinoma, Xeroderma Pigmentosum Group C (XPC)

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Oncotarget

Cigarette Smoke and DNA Repair Deficiency Drive Lung Cancer Development

“Wouldn’t it be cool if …” is an expression the team at Pelotonia say on a regular basis. And, over the years, many of these “what if” ideas have become new programs and events and ways to engage and involve more people. 
“We’ve been cognizant and thoughtful about listening to our community,” said Joe Apgar, CEO of Pelotonia. “We get an amazing amount of feedback from people and that leads to improvements and new things we can do.” In this episode, Apgar talked about all the new things Pelotonia has added in the past few years, including the Challenger platform, kids rides, a gravel ride (October 4 this year) in Hocking Hills that includes a camping option and, for the first time this year, a run/hike/walk. The gravel ride came from a suggestion from Eric Tippett, who has ridden every year and is a member of the JPMorgan Chase team. The idea to add the run/hike/walk was “something we heard from a lot of people,” Apgar said. “They said I don’t ride a bike but if Pelotonia would ever do a run or a walk; I’m in.” The run/hike/walk loop through the woods is at the same location as the gravel ride. “We penciled in 75 people for it, and we already have more than 200 people signed up,” Apgar said. Apgar also talked about the growing number of kids events Pelotonia teams have created with support from the Pelotonia staff. “We think this will be a huge program over time,” Apgar said. The opening ceremony will feature O.A.R., a popular rock band whose members include a few Buckeyes. “I think this will be the most fun opening ceremony we’re ever had,” Apgar said.

Episode 191: Pelotonia Continues to Evolve, Grow & Add New Ways to Engage People, with Joe Apgar

BUFFALO, NY — July 1, 2025 — A new #research paper, featured on the #cover of Aging (Aging-US) Volume 17, Issue 6, was #published on June 4, 2025, titled “DoliClock: a lipid-based aging clock reveals accelerated aging in neurological disorders.”

This study, led by first author Djakim Latumalea from the National University of Singapore and Hanze University of Applied Sciences, with corresponding author Brian K. Kennedy from the National University of Singapore, introduces DoliClock, a biological aging clock based on lipid profiles in the human brain. The researchers found that individuals with autism, schizophrenia, and Down syndrome show signs of accelerated brain aging compared to individuals without these conditions. The discovery offers a new approach to measuring brain aging using lipid markers instead of traditional DNA-based methods.

The team developed DoliClock using lipidomic data from post-mortem prefrontal cortex samples. Lipids are fat-like molecules that play a key role in brain health. Changes in lipid patterns can reflect the biological age of brain tissue. The study focused on a specific class of lipids called dolichols, which increase gradually with age. The DoliClock model was trained to predict biological age by analyzing levels of dolichols and other lipid molecules. It accurately estimated brain age and revealed higher aging rates in individuals with neurological disorders.

One notable finding was a sharp increase in lipid profile variability—also known as entropy—around the age of 40. This suggests a disruption in lipid metabolism during midlife, possibly caused by changes in the mevalonate pathway, a critical biological process involved in producing lipids like cholesterol and dolichol. These disruptions may contribute to aging-related brain decline.

The study also found that dolichol levels could serve as reliable biomarkers of aging. Their consistent increase with age and strong influence on DoliClock’s predictions make them especially useful. In individuals with autism, schizophrenia, and Down syndrome, the clock indicated more advanced biological brain aging than expected, supporting the idea that these conditions are associated with premature aging.

DoliClock offers a new perspective in aging research, complementing existing biological clocks based on DNA or protein markers. Because it relies on lipids, it may detect aspects of aging that other tools cannot. While the current model is based on brain tissue samples, future research may examine whether similar lipid patterns can be identified in more accessible fluids such as blood or cerebrospinal fluid.

“These findings suggest that lipidomics can provide valuable insights into the molecular mechanisms of brain aging and neurological disorders.”

This study highlights the growing potential of lipidomics in the study of aging and neurological disorders. It opens the door to new biomarkers that could help researchers and clinicians better monitor brain aging and develop more targeted interventions for age-related and neurodevelopmental diseases.
DOI - https://doi.org/10.18632/aging.206266

Corresponding author - Brian K. Kennedy - bkennedy@nus.edu.sg

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Aging (Aging-US)

New Lipid-Based Aging Clock Reveals Faster Brain Aging in Autism, Schizophrenia, and Down Syndrome

BUFFALO, NY – July 1, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Optimizing enfortumab vedotin plus pembrolizumab therapy.”

First authors Elias Antoine Karam of the Gustave Roussy and Saint-Joseph University of Beirut and Yaghi César Céline from  the Saint-Joseph University of Beirut, along with their colleagues, reviewed recent developments about treating advanced urothelial carcinoma (aUC), an aggressive form of bladder cancer. Their review highlights how combining enfortumab vedotin and pembrolizumab as a first-line treatment offers a major improvement for patients with limited options and poor prognoses.

Advanced urothelial cancer has traditionally been treated with platinum-based chemotherapy, which often causes serious side effects and offers limited long-term benefit. Many patients are even ineligible for it due to underlying health conditions. The new combination presents a more effective and better-tolerated alternative, as shown in recent clinical trials reviewed by the authors.

Enfortumab vedotin targets Nectin-4, a protein present in most urothelial cancer cells, delivering a cancer-killing agent directly into tumors. Pembrolizumab helps the immune system detect and destroy cancer cells. Together, they have shown strong results in extending survival with fewer serious side effects than chemotherapy. These findings led to FDA approval in 2023 for use in a broad range of patients, including those unable to tolerate traditional treatments.

“In the phase II KEYNOTE-052 study, pembrolizumab demonstrated significant efficacy as initial therapy in patients with aUC who were ineligible for a cisplatin-based regimen.”

The review also compares this new approach with other evolving strategies, such as therapies using nivolumab and chemotherapy combinations. Among current first-line options, enfortumab vedotin and pembrolizumab have produced the most promising outcomes. However, the best course of action following disease progression remains unclear.

Other important challenges raised in the review include the high cost of the new therapies, limited patient access to them, and the absence of reliable biomarkers to predict individual response. The authors call for further studies to refine treatment strategies and explore blood-based tools that could guide therapy decisions and minimize side effects.

This review offers a clear summary of how recent clinical advances are reshaping the treatment of aUC. It reflects a shift away from traditional chemotherapy toward immunotherapy and targeted, personalized treatments that aim to extend survival and improve quality of life.

DOI - https://doi.org/10.18632/oncotarget.28741

Correspondence to - Elias Antoine Karam - eliaskaram18@gmail.com

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Keywords - cancer, advanced urothelial carcinoma (aUC), enfortumab vedotin, pembrolizumab, treatment strategies, bladder cancer

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New Drug Combination Redefines First-Line Treatment for Advanced Urothelial Cancer

BUFFALO, NY — July 2, 2025 — A new #research perspective was #published in Aging (Aging-US) Volume 17, Issue 6, on May 29, 2025, titled “Peto’s paradox’s relevance is off the scale.”

In this perspective, Dr. Mirre J.P. Simons from the University of Sheffield argues that Peto’s paradox—a well-known concept in cancer biology—remains a vital framework for understanding cancer resistance in large animals. Dr. Simons challenges recent claims that dismiss the paradox and emphasizes that the unexpectedly low cancer rates in large species still require explanation. This insight is especially relevant for aging and cancer research.

Peto’s paradox highlights a puzzling observation: larger animals like elephants and whales, despite having far more cells than smaller animals, do not have proportionally higher cancer rates. If each cell had an equal chance of turning cancerous, bigger animals should develop cancer much more frequently. But in reality, they do not. This suggests that evolution has equipped these animals with powerful biological defenses against cancer.

“The field of comparative biology into ageing and cancer was given a strong impetus when Peto identified that humans have substantially more cells than mice, but do not have substantially larger incidence of cancer.”

Dr. Simons explains that recent studies showing small increases in cancer with body size do not disprove the paradox. The expected increase, based on basic mathematical models, would be massive—many times greater than what is observed. Instead of rejecting Peto’s paradox, the field should focus on understanding how large animals suppress cancer so effectively.

The author points out that the key to resolving this paradox may lie in traits that evolved alongside body size, such as tissue environments or specialized cell-control mechanisms. These features might reduce the probability of cancer developing, even in animals with millions or billions more cells than humans.

Importantly, this perspective underscores the clinical potential of studying species that resist cancer naturally. Studying these natural defenses may help researchers uncover new ways to understand, prevent, or manage cancer. Because cancer risk increases with age in most species, understanding how some animals limit both aging and cancer may also help explain how these two processes are connected.

Dr. Simons cautions against oversimplifying cancer biology by focusing only on genetic mutations. Instead, understanding how cells interact with their environment, known as the tissue microenvironment, may offer deeper insight into how cancer develops or is prevented.

By reaffirming the importance of Peto’s paradox, this research perspective encourages the scientific community to explore the evolutionary tools nature uses to fight cancer. These insights could improve our understanding of cancer and inspire new strategies to support healthier aging.

DOI - https://doi.org/10.18632/aging.206258

Corresponding author - Mirre J.P. Simons - m.simons@sheffield.ac.uk

Video short - https://www.youtube.com/watch?v=sDaq07zX2TM

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Keywords - aging, cancer, evolution

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Why Big Animals Do Not Get More Cancer: Revisiting Peto’s Paradox

Liver cancer, especially hepatocellular carcinoma (HCC), remains a major health concern worldwide. In Latin America, the situation becomes more difficult due to limited access to advanced treatments and the high prevalence of underlying liver diseases. A recent research paper, published in Volume 16 of Oncotarget by researchers from Argentina, Brazil, Chile, and Colombia, offers valuable insights into how patients in the region respond to a widely used immunotherapy regimen. This real-world study explores both the effectiveness of treatment and the risks of immune-related side effects.

Understanding Hepatocellular Carcinoma: Why It is So Difficult to Treat

Hepatocellular carcinoma is often diagnosed at an advanced stage and frequently occurs in people with pre-existing liver conditions such as cirrhosis. Standard treatments like surgery or local therapies are not always possible in these cases. In recent years, the combination of two drugs—atezolizumab and bevacizumab—has shown promise in extending survival. However, most of the evidence comes from controlled clinical trials that may not represent the realities faced by healthcare providers and patients in Latin America.

The Study: Immunotherapy for Hepatocellular Carcinoma in Latin America

In a multicenter study titled “Immune-mediated adverse events following atezolizumab and bevacizumab in a multinational Latin American cohort of unresectable hepatocellular carcinoma,” led by Leonardo Gomes da Fonseca from Hospital das Clínicas, Universidade de São Paulo, Brazil, and Federico Piñero from Hospital Universitario Austral, Argentina, researchers aimed to fill that gap. The study included 99 patients with advanced HCC from Argentina, Brazil, Chile, and Colombia. All patients received the combination of atezolizumab and bevacizumab. The main objectives were to assess how frequently immune-related side effects, known as immune-related adverse events (irAEs), occurred and whether these events affected overall survival.

Full blog - https://www.oncotarget.org/2025/07/02/immunotherapy-safety-for-hepatocellular-carcinoma-in-latin-america-insights-from-a-real-world-study/

Paper DOI - https://doi.org/10.18632/oncotarget.28721

Correspondence to - Federico Piñero - fpinerof@cas.austral.edu.ar

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Keywords - cancer, liver cancer, immunotherapy, adverse events, immunology, real-world 

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Immunotherapy Safety for Hepatocellular Carcinoma in Latin America: Insights from a Real-World Study

Dr. Andres Cardenas, from the Department of Epidemiology and Population Health at Stanford University, joins host Dr. Evgeniy Galimov to discuss a research paper he co-authored in Volume 17, Issue 2 of Aging (Aging-US), titled “Exposome-wide association study of environmental chemical exposures and epigenetic aging in the National Health and Nutrition Examination Survey.”

DOI - https://doi.org/10.18632/aging.206201

Corresponding author - Andres Cardenas - andresca@stanford.edu

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Longevity & Aging Series - https://www.aging-us.com/longevity

Abstract

Epigenetic clocks can serve as pivotal biomarkers linking environmental exposures with biological aging. However, research on the influence of environmental exposures on epigenetic aging has largely been limited to a small number of chemicals and specific populations. We harnessed data from the National Health and Nutrition Examination Survey 1999-2000 and 2001-2002 cycles to examine exposome-wide associations between environmental exposures and epigenetic aging. A total of 8 epigenetic aging biomarkers were obtained from whole blood in 2,346 participants ranging from 50-84 years of age. A total of 64 environmental exposures including phthalates, metals, pesticides, dioxins, and polychlorinated biphenyls (PCBs) were measured in blood and urine. Associations between log2-transformed/standardized exposure measures and epigenetic age acceleration (EAA) were assessed using survey-weighted generalized linear regression. A 1 standard deviation (SD) increase in log2 serum cadmium levels was associated with higher GrimAge acceleration (beta = 1.23 years, p = 3.63e-06), higher GrimAge2 acceleration (beta = 1.27 years, p = 1.62e-05), and higher DunedinPoAm (beta = 0.02, p = 2.34e-05). A 1 SD increase in log2 serum cotinine levels was associated with higher GrimAge2 acceleration (beta = 1.40 years, p = 6.53e-04) and higher DunedinPoAm (beta = 0.03, p = 6.31e-04). Associations between cadmium and EAA across several clocks persisted in sensitivity models adjusted for serum cotinine levels, and other associations involving lead, dioxins, and PCBs were identified. Several environmental exposures are associated with epigenetic aging in a nationally representative US adult population, with particularly strong associations related to cadmium and cotinine across several epigenetic clocks.

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Keywords - aging, epigenetic aging, environmental exposures, exposome, epigenetics

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Longevity & Aging Series (S3, E5): Dr. Andres Cardenas

Could hacking a tick’s biology help prevent the next outbreak? In this episode of the YJBM, we sit down with Emily Johnson to travel across the scale of life, all the way from the environment that surrounds us to a molecular pathway called kinase signaling. We dive into the fundamentals of vector biology and the transmission of diseases like Lyme. We also discuss the tools and technologies driving the field forward, from mRNA vaccines to the potential of AI, and what the future holds for understanding disease and transmission through the lens of signaling pathways.

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Kinase Pathways Driving the Future of Tick Control: Interview with Emily Johnson

BUFFALO, NY - July 7, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Genetic characteristics of blastic plasmacytoid dendritic cell neoplasm: A single institution experience.”

In this study, a research team led by first author Fei Fei and corresponding author Michelle Afkhami from the City of Hope Comprehensive Cancer Center investigated a rare and aggressive type of blood cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN). Their research uncovered frequent mutations in key genes and identified CCDC50 as a potential biomarker for diagnosis and disease monitoring. These findings could help improve how this cancer is detected and treated in the future.

BPDCN most often affects older adults and is known for its rapid progression and poor survival rates. The researchers performed genetic sequencing on 21 patients to better understand the disease. They found that two genes, TET2 and ASXL1, were frequently mutated in these patients and were linked to worse survival, especially in those over 65 years old.

“Our study revealed that TET2 (57%) and ASXL1 (33%) were the most frequently mutated genes, followed by NRAS (29%), SRSF2 (14%), ZRSR2 (14%), and KMT2D (14%).”

The study also discovered that a gene called CCDC50 was expressed at much higher levels in BPDCN samples compared to other blood cancers, such as acute myeloid leukemia and chronic monomyelocytic leukemia. This suggests that CCDC50 may help clinicians distinguish BPDCN from other similar diseases. Importantly, CCDC50 levels dropped significantly in patients whose disease went into remission, highlighting its potential as a tool for tracking disease activity over time.

Researchers further observed that patients who received stem cell transplants lived longer than those who did not, reinforcing the importance of this treatment approach. However, BPDCN remains a challenging disease with an overall poor outlook, making these findings an important step toward better care.

This research provides new insights into the genetic changes behind BPDCN and points to CCDC50 as a promising marker to improve diagnosis and monitor treatment success. Larger studies will be needed to confirm these results and bring these discoveries closer to use in routine medical practice.

DOI - https://doi.org/10.18632/oncotarget.28742

Correspondence to - Michelle Afkhami - mafkhami@coh.org

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Keywords - cancer, Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Next-generation sequencing (NGS), CCDC50

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Key Genetic Alterations and Biomarker for Blastic Plasmacytoid Dendritic Cell Neoplasm

A new study published recently as the cover of Aging Volume 17, Issue 6, describes a new method to estimate how fast the brain is aging. By analyzing lipids, or fat molecules, in brain tissue, researchers from the National University of Singapore and Hanze University of Applied Sciences created a biological “clock” called DoliClock. This innovation highlights how conditions such as autism, schizophrenia, and Down syndrome are associated with accelerated brain aging.

Understanding Brain Aging

As people grow older, their brains naturally change. However, in many neurological disorders, these changes seem to appear earlier and progress more rapidly. Disorders like autism, schizophrenia, and Down syndrome reduce quality of life and contribute to premature death. Scientists have long searched for better ways to measure biological age in the brain to understand these processes and develop strategies to slow them down.

Most existing methods for estimating biological age rely on genetic markers, such as DNA methylation, which are chemical modifications of DNA. While useful, these approaches may not fully capture the complexity of aging, especially in the brain. Lipids, which are essential components of brain cells and play important roles in energy storage and signaling, offer another perspective.

Full blog - https://aging-us.org/2025/07/doliclock-a-lipid-based-clock-for-measuring-brain-aging/

Paper DOI - https://doi.org/10.18632/aging.206266

Corresponding author - Brian K. Kennedy - bkennedy@nus.edu.sg

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Keywords - aging, aging clock, down syndrome, autism, schizophrenia, dolichol

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DoliClock: A Lipid-Based Clock for Measuring Brain Aging

BUFFALO, NY — July 8, 2025 — A new #research paper was #published in Aging (Aging-US) Volume 17, Issue 6, on May 30, 2025, titled “Impact of waist-to-hip and waist-to-height ratios on physical performance: insights from the Longevity Check-up 8+ project.”

In this study, researchers led by first author Anna Maria Martone and corresponding author Elena Levati from the Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS and Università Cattolica del Sacro Cuore found that adults with higher waist-to-hip and waist-to-height ratios tend to have poorer physical performance. These simple body shape measures emerged as important tools for assessing strength and mobility, which are essential for maintaining independence as people age.

The analysis included data from more than 10,000 Italian adults aged 18 to 98 years who participated in the Longevity Check-up 8+ project, a nationwide health initiative aimed at promoting healthy lifestyles and raising awareness of cardiovascular risks. Researchers measured participants’ waist-to-hip (WHR) and waist-to-height (WHtR) ratios and assessed their physical function using the five-repetition chair stand test, a standard evaluation of lower body strength and mobility.

“Among 10690 participants (mean age 57.0 ± 14.8 y; 54% females), men exhibited higher WHR and WHtR and a higher prevalence of abnormal values (61% and 71%).”

The results showed that individuals with higher waist-to-hip and waist-to-height ratios took longer to complete the test, reflecting reduced physical function. Even after adjusting for lifestyle factors such as diet, exercise habits, and cardiovascular health, these ratios remained strongly linked to poorer performance. The waist-to-height ratio, in particular, proved to be a more effective predictor of physical ability across different age and gender groups.

These findings highlight how abdominal fat, already tied to serious health risks like heart disease and diabetes, may also impair mobility and independence as people age. Monitoring waist measurements could help identify individuals at risk of functional decline, offering a simple tool to support public health in aging populations.

The waist-to-height ratio is especially valuable because of its simplicity and practicality. Requiring only waist and height measurements, it can be easily used in clinical settings and community health programs to screen for potential mobility issues. Encouraging healthy waist sizes through balanced diets and regular exercise could help preserve physical performance and delay age-related decline. These findings may guide future prevention strategies. By identifying individuals at higher risk, healthcare professionals can implement targeted interventions to support long-term health and independence.

DOI - https://doi.org/10.18632/aging.206260

Corresponding author - Elena Levati - elena.levati01@icatt.it

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Keywords - aging, physical performance, body composition, waist-to-hip ratio, waist-to-height ratio, chair-stand test

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