Senescence-Related TME Genes as Key Prognostic Predictors in HNSCC

In a new study, researchers aimed to investigate the prognostic significance of senescence-related TME genes in head and neck squamous cell carcinoma (HNSCC) and their potential implications for immunotherapy response. 

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and heterogeneous form of cancer that affects thousands of individuals worldwide. The prognosis for HNSCC patients can vary greatly, depending on factors such as tumor stage and site. The tumor microenvironment (TME) plays a crucial role in tumorigenesis and disease progression, with cellular senescence being a key component. Senescent cells, characterized by cell-cycle arrest, have been shown to have both tumor-suppressive and tumor-promoting effects. However, the prognostic significance of senescence-related TME genes in HNSCC remains poorly understood.

In a new study, researchers Young Chan Lee, Yonghyun Nam, Minjeong Kim, Su Il Kim, Jung-Woo Lee, Young-Gyu Eun, and Dokyoon Kim from Kyung Hee University, Kyung Hee University Hospital at Gangdong, and the University of Pennsylvania aimed to investigate the prognostic significance of senescence-related TME genes in HNSCC and their potential implications for immunotherapy response. They utilized data from The Cancer Genome Atlas (TCGA) to identify two distinct subtypes of HNSCC based on the expression of senescence-related TME genes. The team then constructed a risk model consisting of senescence-related TME core genes (STCGs) and validated its prognostic capability in independent cohorts. Their research paper was chosen as an Aging cover paper and published in Volume 16, Issue 2, entitled, “Prognostic significance of senescence-related tumor microenvironment genes in head and neck squamous cell carcinoma.”

“To the best of our knowledge, this is the first study to offer a comprehensive evaluation of the senescence related TME status by integrating senescence related TME genes through a gene-gene network and clustering. Furthermore, we have introduced a novel risk model that utilizes a selected gene set to predict prognosis and confirmed the expression of STCGs in immune cells at single-cell levels.”

The Study

Identification of Prognostic Senescence-Related TME Genes

To identify prognostic senescence-related TME genes, the researchers screened a total of 7,878 genes in the TCGA-HNSCC dataset. They identified 288 genes that belonged to TME-related genes, tumor-associated senescence (TAS) genes, and immune-related genes. From these genes, they selected 91 prognostic senescence-related TME genes (PSTGs) based on differential expression analysis and Cox regression analysis.

Senescence-Related TME Subtypes and Characterization

Using consensus clustering analysis, the researchers classified the HNSCC samples into two distinct subtypes based on the expression of PSTGs: subtype 1 and subtype 2. The two subtypes exhibited significant differences in clinical and molecular characteristics. Subtype 2 had a higher prevalence of HPV-positive and oropharyngeal cancer cases, while subtype 1 was characterized by a higher proportion of advanced tumor stage and overall stage.

Further analysis revealed distinct differences between the subtypes in terms of genetic alterations, methylation patterns, enriched pathways, and immune infiltration. Subtype 1 had a higher mutation rate in the TP53 gene and exhibited hypomethylation in several CpG sites compared to subtype 2. Additionally, subtype 2 showed higher immune scores, stromal scores, and ESTIMATE scores, indicating a more favorable immune microenvironment.

The two subtypes also displayed differences in survival outcomes. Kaplan-Meier survival analysis showed that subtype 2 had a more favorable overall survival compared to subtype 1. This difference was enhanced in the HPV-positive cohort, suggesting that the senescence-related TME subtypes may have implications for prognosis in specific patient subgroups.

Risk Scoring Based on Senescence-Related TME Status

Using the 91 PSTGs, the researchers constructed a risk scoring model based on the LASSO Cox regression algorithm. They identified 21 STCGs that were associated with either increased risk or protection. The risk scores based on the expression levels of these genes were calculated for each patient, and the patients were classified into high- and low-risk groups.

The prognostic performance of the risk scoring model was tested in independent cohorts, including the TCGA-HNSCC test set, the GSE41613 cohort, and the KHUMC cohort. The high-risk group showed significantly lower overall survival compared to the low-risk group in the TCGA-HNSCC test set and the GSE41613 cohort. Although not statistically significant, the low-risk group demonstrated a trend towards higher overall survival in the KHUMC cohort.

Immunotherapy Response Prediction and Single-Cell Analysis

The team also investigated the immunotherapy response prediction based on the risk model and the expression of STCGs. They found that the low-risk group had higher immunophenoscores and a significantly higher proportion of responders to immunotherapy compared to the high-risk group.

To further evaluate the senescence-related TME characteristics at the single-cell level, the researchers analyzed single-cell transcriptome data from HNSCC tissue. They found that STCGs were enriched in fibroblast, mono/macrophage, and T cell populations, suggesting that these cell types contribute to the senescent features of HNSCC.

Conclusion

In conclusion, the study sheds light on the prognostic significance of senescence-related TME genes in HNSCC. Their findings highlight the heterogeneity of HNSCC and the importance of the senescence-related TME in prognosis and immunotherapy response. The risk scoring model based on STCGs provides a potential prognostic biomarker for HNSCC patients, and the single-cell analysis further elucidates the association between STCGs and specific cell populations within the TME. These findings contribute to a deeper understanding of the complex interplay between senescence and the TME in HNSCC and have implications for precision medicine and personalized treatment approaches. Further research and validation are needed to fully understand the clinical implications of senescence-related TME genes in HNSCC. However, this study provides valuable insights into the role of cellular senescence in tumor progression and the potential for targeting senescence-related pathways in the development of novel therapeutic strategies for HNSCC patients.

“In conclusion, this study comprehensively investigated the prognostic and immunological features of senescence related TME genes in HNSC. By leveraging these senescence related TME genes, we successfully developed a risk model to predict HNSC prognosis and immunotherapy response, which was robustly validated using external transcriptome datasets. These findings provided evidence for the role of senescence in the TME and highlighted the potential of senescence-related biomarkers as promising therapeutic targets.”

Click here to read the full research paper published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Efficacy and Safety of EGFR-TKIs for Elderly Patients With NSCLC

In a new study, researchers investigated the effectiveness and safety of EGFR-tyrosine kinase inhibitors in elderly patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC).

Lung cancer is a significant global health issue, being the second most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) represents the majority of lung cancer cases and is often diagnosed at an advanced stage. Epidermal growth factor receptor (EGFR) mutations are more common in Asian NSCLC populations than in Western populations. 

Activating EGFR mutations, such as exon 19 deletions and L858R, are predictive of response to tyrosine kinase inhibitors (TKIs) and have revolutionized the treatment landscape for patients with EGFR-mutated NSCLC. However, most clinical trials tend to lack data for the elderly population, even though a significant proportion of lung cancer patients are aged 65 years and older. This underrepresentation of elderly patients in clinical trials limits our understanding of the effectiveness and safety of EGFR-TKIs in this specific population.

In this new study, researchers Ling-Jen Hung, Ping-Chih Hsu, Cheng-Ta Yang, Chih-Hsi Scott Kuo, John Wen-Cheng Chang, Chen-Yang Huang, Ching-Fu Chang, and Chiao-En Wu from Chang Gung University and Taoyuan General Hospital conducted a multi-institute retrospective study to investigate the effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with EGFR-mutated advanced NSCLC. On January 8, 2024, their research paper was published in Aging’s Volume 16, Issue 1, entitled, “Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.”

“[…] comparisons of the effectiveness and safety of these EGFR-TKIs approved for patients aged ≥65 years are limited. The available real-world evidence for EGFR-TKI treatment of elderly patients is also limited. Therefore, this study aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients (aged ≥65 years) with EGFR-mutated advanced NSCLC.”

The Study

In this study, 1,343 treatment-naïve patients with EGFR-mutated advanced NSCLC were enrolled from multiple hospitals in Taiwan. The patients were divided into four age groups: <65 years, 65-74 years, 75-84 years, and ≥85 years. Patient characteristics, including sex, smoking history, performance status, tumor involvement, EGFR mutation type, metastatic sites, and choice of EGFR-TKI, were compared among the age groups.

The researchers found that afatinib was more effective than gefitinib and erlotinib in elderly patients aged ≥65 years, as evidenced by longer median progression-free survival (PFS) and overall survival (OS). The median PFS for afatinib was 14.7 months, compared to 9.9 months for gefitinib and 10.8 months for erlotinib (p = 0.003). Similarly, the median OS for afatinib was 22.2 months, compared to 17.7 months for gefitinib and 18.5 months for erlotinib (p = 0.026).

Further analysis by age subgroup revealed that the significant differences in PFS and OS were primarily driven by patients aged 65-74 years. In this age group, afatinib demonstrated superior efficacy compared to gefitinib and erlotinib, with a median PFS of 14.7 months and median OS of 22.2 months (p = 0.032 for PFS, p = 0.018 for OS). While afatinib showed greater effectiveness, it was also associated with more adverse events (AEs) compared to gefitinib and erlotinib. The study reported a higher incidence of grade ≥3 AEs, including skin toxicities, paronychia, mucositis, and diarrhea, in patients receiving afatinib. Notably, patients receiving afatinib also required more dose reductions or discontinuation due to AEs.

Various factors were identified as independent prognostic factors of PFS and OS in elderly patients with EGFR-mutated advanced NSCLC. A performance status score of 2-4, stage IV disease, liver, bone, pleural, adrenal, and pericardial metastasis, and treatment with gefitinib were associated with worse PFS and OS.

Conclusion

This large retrospective study provides valuable real-world evidence on the effectiveness and safety of EGFR-TKIs in elderly patients with EGFR-mutated advanced NSCLC. The findings suggest that afatinib is more effective as a first-line treatment than gefitinib or erlotinib for elderly patients, particularly those aged 65-74 years. However, it is important to consider the increased risk of adverse events associated with afatinib in this population. These results highlight the need for individualized treatment decisions for elderly patients with NSCLC. Clinicians should carefully consider the patient’s age, performance status, and comorbidities when selecting an appropriate EGFR-TKI. Additionally, close monitoring of AEs and appropriate management strategies are crucial to ensure optimal treatment outcomes in this population.

“In conclusion, this study demonstrated the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that has often been underrepresented in clinical trials and real-world evidence. For elderly patients with EGFR-mutated advanced NSCLC, clinicians were more likely to prefer gefitinib or erlotinib to afatinib as a therapy, in contrast to the treatment regimen for younger patients. Nevertheless, afatinib still emerged as the primary choice for first-line treatment for older patients compared to other EGFR-TKIs, as it is more effective than gefitinib or erlotinib in elderly patients with EGFR-mutated advanced NSCLC.”

Click here to read the full research paper published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Rooted in Chinese Medicine: Zicao’s Anti-Cancer Effects on Lung Cancer

In this new study, researchers investigated a plant used in traditional Chinese medicine and its anti-cancer effects in non-small cell lung cancer (NSCLC).

Traditional Chinese medicine has long been explored for its potential in treating various diseases, including cancer. Lithospermum erythrorhizon, or purple gromwell, is a mysterious plant native to East Asia, and its dried root is often referred to as Zicao. Acetylshikonin, a compound derived from Zicao, has shown promise in exhibiting a variety of anti-cancer properties. While the effects of acetylshikonin on lung cancer are not yet fully understood, recent research has shed light on its potential as a therapeutic agent. 

In a new study, researchers Shih-Sen Lin, Tsung-Ming Chang, Augusta I-Chin Wei, Chiang-Wen Lee, Zih-Chan Lin, Yao-Chang Chiang, Miao-Ching Chi, and Ju-Fang Liu from Shin Kong Wu Ho-Su Memorial Hospital, Chang Gung Memorial Hospital, Chang Gung University of Science and Technology, Ming Chi University of Technology, Taipei Medical University, and China Medical University aimed to explore the mechanisms underlying acetylshikonin-induced cell death in non-small cell lung cancer (NSCLC). On December 19, 2023, their research paper was published in Aging’s Volume 15, Issue 24, entitled, “Acetylshikonin induces necroptosis via the RIPK1/RIPK3-dependent pathway in lung cancer.”

“This study explored the mechanisms underlying acetylshikonin-induced cell death in non-small cell lung cancer (NSCLC).”

Acetylshikonin and Cell Viability Reduction

In this study, researchers investigated the effects of acetylshikonin on the viability of NSCLC cells. The researchers treated H1299 and A549 cells with varying concentrations of acetylshikonin and assessed cell viability using a cell counting kit-8 (CCK-8) assay. The results showed that acetylshikonin significantly reduced cell viability in a dose-dependent manner. The IC50 values for H1299 and A549 cells were determined to be 2.34 μM and 3.26 μM, respectively. These findings suggest that acetylshikonin has the potential to effectively reduce the viability of lung cancer cells without causing significant damage to normal cells.

Cell Death Induction by Acetylshikonin

To further investigate the effects of acetylshikonin on NSCLC cells, the team examined the morphological changes associated with cell death. They observed that acetylshikonin treatment led to chromatin condensation, cell shrinkage, and the formation of cell debris, indicating cell death. Additionally, Annexin V/propidium iodide (PI) staining demonstrated an increase in the population of cells positive for Annexin V and PI, suggesting the induction of both apoptotic and necrotic cell death. Further analysis revealed that acetylshikonin increased membrane permeability, as evidenced by the uptake of PI by the cells. These findings indicate that acetylshikonin promotes cell death in NSCLC cells, potentially through necrotic pathways.

Acetylshikonin and Cell Cycle Arrest

In addition to its effects on cell viability and cell death, acetylshikonin was found to induce cell cycle arrest in NSCLC cells. The researchers examined the cell cycle progression of H1299 and A549 cells treated with acetylshikonin. Flow cytometry analysis revealed an increase in the proportion of cells in the subG1 and G2/M phases, indicating DNA fragmentation and cell cycle arrest in the G2/M phase. Western blot analysis further confirmed these findings by showing a decrease in the expression of cell cycle regulatory proteins, CDK1 and cyclin B1, in acetylshikonin-treated cells. These results suggest that acetylshikonin exerts its anti-cancer effects by inducing cell cycle arrest, thereby inhibiting cancer cell proliferation.

Oxidative Stress and Mitochondrial Dysfunction

The team also investigated the involvement of oxidative stress and mitochondrial dysfunction in acetylshikonin-induced cell death. Acetylshikonin treatment was found to increase intracellular reactive oxygen species (ROS) levels in NSCLC cells. This increase in ROS was associated with a decrease in mitochondrial membrane potential (MMP), indicating mitochondrial dysfunction. These findings suggest that acetylshikonin induces oxidative stress and disrupts mitochondrial function in NSCLC cells, potentially contributing to cell death.

Lipid Peroxidation and GPX4 Expression

The researchers explored the role of lipid peroxidation and the expression of glutathione peroxidase 4 (GPX4) in acetylshikonin-induced cell death. They observed that acetylshikonin treatment caused lipid peroxidation, as evidenced by the quenching of red fluorescence in BODIPY™ 581/591 C11-stained cells. This lipid peroxidation was associated with a decrease in GPX4 expression. GPX4 is an enzyme involved in maintaining cellular homeostasis and protecting against oxidative stress. The downregulation of GPX4 in NSCLC cells treated with acetylshikonin suggests a potential mechanism for inducing cell death.

Necroptosis Pathway Activation by Acetylshikonin

The team further investigated the mechanism by which acetylshikonin induces cell death in NSCLC cells. They found that acetylshikonin promoted the phosphorylation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like kinase (MLKL). These proteins are key players in the necroptosis signaling pathway. Immunofluorescence staining showed an increase in MLKL phosphorylation in acetylshikonin-treated cells, while Western blot analysis confirmed the activation of RIPK1, RIPK3, and MLKL. Importantly, pretreatment with RIPK1 inhibitors reversed the phosphorylation of MLKL and significantly attenuated cell death induced by acetylshikonin, suggesting that the activation of the RIPK1/RIPK3/MLKL cascade is involved in the necroptotic cell death pathway triggered by acetylshikonin.

Conclusion

In conclusion, acetylshikonin exhibits promising anti-cancer effects in NSCLC cells. It reduces cell viability, induces cell death, and promotes cell cycle arrest in the G2/M phase. Acetylshikonin also increases membrane permeability and activates the necroptosis signaling pathway through the phosphorylation of RIPK1, RIPK3, and MLKL. Furthermore, acetylshikonin induces oxidative stress, disrupts mitochondrial function, and promotes lipid peroxidation. These findings suggest that acetylshikonin holds potential as a therapeutic agent for the treatment of lung cancer. Further research is warranted to explore the clinical applications of acetylshikonin and its potential synergistic effects with existing lung cancer therapies.

“We determined that even low doses of acetylshikonin reduced the viability of lung cancer cells without significantly affecting normal cells. When used to treat lung cancer, acetylshikonin was shown to promote cell death and arrest cell cycle progression in the G2/M phase.”

Click here to read the full research paper published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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For media inquiries, please contact media@impactjournals.com.

Understanding the Mechanisms of Brain Aging and Longevity in Neurons

In a new editorial, researchers discuss interconnected mechanisms of neuronal functionality and available tools to investigate neuronal aging and longevity. 

Neurons, the building blocks of the nervous system, play a vital role in our body’s function and longevity. Unlike other cells, neurons do not undergo replicative aging. However, they are still susceptible to various sources of damage throughout life, leading to neuronal death. Understanding the mechanisms behind aging and neuronal death is crucial for uncovering the secrets of brain longevity and developing potential interventions to promote healthy aging.

In a new editorial, researchers Fang Fang, Robert Usselman and Renee Reijo Pera from University of Science and Technology of China, Florida Institute of Technology and McLaughlin Research Institute discussed new interconnected mechanisms of neuronal functionality and available tools to investigate neuronal aging and longevity. On December 13, 2023, their editorial was published in Aging’s Volume 15, Issue 23, entitled, “Aging and neuronal death.”

Neuronal Durability, Differentiation & Maintenance

Neurons, born during embryonic development, must function in the body for the entire lifespan of the organism. They are incredibly durable cells, but they are not immune to damage. Neurons require a significant amount of oxygen and glucose to carry out their activities, making them vulnerable to ischemia. Ischemia occurs when the blood supply to a particular tissue is restricted, leading to oxygen and nutrient deprivation. 

Neurons can accumulate damage over time, which may result in cell death linked to reactive oxygen species (ROS). Neurons may also die due to ion overload and swelling caused by the malfunction of voltage-gated ion channels on their membranes. High concentrations of neurotransmitters and the accumulation of misfolded proteins are also implicated in neuronal death, observed in various neurodegenerative diseases.

To gain insights into the factors that promote neuron differentiation and maintenance, researchers have developed innovative screening methods. For example, Cui and colleagues described a high-throughput screening method using a luciferase reporter construct inserted downstream of the endogenous tyrosine hydroxylase (TH) gene. They differentiated neurons from human pluripotent stem cells and monitored their activity over time. This approach allows for the modeling of cell survival and demise, providing valuable information about the factors that influence neuronal longevity.

The Role of ROS in Survival & Death

Reactive oxygen species (ROS) are molecules produced during normal cellular metabolism. They play a crucial role in various biological processes but can also lead to oxidative stress when their levels exceed normal functional levels. Recent research has shed light on the distinction between global and local ROS balances and imbalances in cell phenotyping and mitochondrial energy management.

While global ROS homeostasis is essential for overall cellular health, ROS signaling pathways are driven locally by cellular microdomain-specific ROS production and degradation. Neurons have developed mechanisms to control ROS production and combat oxidative stress. For example, they express neurotrophic proteins that enhance mitochondrial activity, promoting the overall health of neurons.

“A sustained disruption of ROS balance can result in desirable enhanced cell signaling or undesirable oxidative stress, which can either improve function or diminish performance, respectively.”

Mechanisms for Longevity

Neurons have evolutionarily developed intricate mechanisms to maintain their longevity. They possess a distinct transcriptome signature that represses genes related to neural excitation and synaptic function. By preventing neurons from experiencing ion overload, this mechanism contributes to their long-term survival.

These brain cells have also developed specific DNA repair mechanisms to correct errors induced by active transcription. Neurons can turn off pro-apoptotic genes through alternative splicing, avoiding apoptosis and promoting long-term survival. These interconnected mechanisms work together to reduce the accumulation of aging-related damage in neurons. Understanding the fundamental mechanisms that enable the longevity of neurons is crucial for developing interventions that promote healthy brain aging. Researchers can use novel tools, including cell-based models, imaging techniques and animal studies, to investigate these mechanisms.

Conclusions

Neurons, although durable cells, are susceptible to various forms of damage that can lead to their demise. By studying the interplay between ROS, neuronal excitation, DNA repair, and apoptosis, researchers aim to uncover the secrets of brain longevity and develop strategies to mitigate the effects of aging on neurons. By understanding these mechanisms, researchers aim to develop interventions that promote healthy brain aging and enhance our overall understanding of brain health.

“Together, these findings suggest that neurons have evolved a set of intrinsically interconnected mechanisms to reduce long-term accumulations of aging-related damages. Disruption in these mechanisms may tip the neuron homeostasis off-balance and drive the neurons into the path of degeneration. We have a plethora of tools to probe the fundamental mechanisms with hopes of translation to clinical applications.”

Click here to read the full editorial published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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What Makes Children of Older Fathers at Increased Risk of Autism?

In this new study, researchers investigated the relationship between paternal age, the BEGAIN gene and autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication and social interaction, as well as repetitive behaviors. It has been observed that children born to older fathers have an increased risk of developing ASD and other neurodevelopmental disorders. This phenomenon suggests that paternal age may have an impact on the risk of ASD in offspring.

Recent research has focused on understanding the potential mechanisms underlying the association between paternal age and ASD. One area of interest is the epigenome, specifically DNA methylation, which refers to the addition or removal of methyl groups to DNA molecules. DNA methylation can affect gene expression and play a role in various biological processes.

In a new study, researchers Ramya Potabattula, Andreas Prell, Marcus Dittrich, Caroline Nava, Christel Depienne, Yosra Bejaoui, Nady El Hajj, Thomas Hahn, Martin Schorsch, and Thomas Haaf from Julius Maximilians University, Groupe Hospitalier Pitié-Salpêtrière, University Hospital Essen, Hamad Bin Khalifa University, and Fertility Center in Wiesbaden, Germany, explored the relationship between paternal age, DNA methylation of the BEGAIN gene, and the risk of ASD. The BEGAIN gene encodes a protein involved in protein-protein interactions at synapses, which are crucial for proper brain function. On November 28, 2023, their research paper was published in Aging’s Volume 15, Issue 22, entitled, “Effects of paternal and chronological age on BEGAIN methylation and its possible role in autism.”

“So far, only 40 genes with sperm ageDMRs [age-associated differentially methylated regions] have been replicated in at least three independent genome-wide methylation screens [19], which makes them primary candidates for mediating paternal age effects on the next generation. Here, we focused on one of these top candidates, the BEGAIN promoter region.”

The Study

The study focused on examining the impact of paternal age on BEGAIN methylation. Various techniques were employed to investigate this relationship. Sperm samples from normozoospermic individuals attending a fertility center were analyzed. The researchers aimed to understand how paternal age influences BEGAIN methylation, specifically observing its trends in sperm.

To extend their exploration of transgenerational effects, fetal cord blood samples were also examined. The team aimed to discern whether paternal age influenced BEGAIN methylation differently in male and female offspring. The research team employed meticulous analyses to understand the sex-specific patterns associated with paternal age and BEGAIN methylation.

They also delved into the effects of chronological age on BEGAIN methylation. Peripheral blood samples from individuals of different ages were analyzed to investigate the relationship between chronological age and BEGAIN methylation. The study aimed to discern whether BEGAIN methylation undergoes changes with age in a sex-specific manner.

“It is tempting to speculate that transmission of paternal age-associated sperm methylation changes into the next generation modulates BEGAIN regulation and susceptibility to neurodevelopmental disorders.”

The Results

The research yielded significant findings. A negative correlation between paternal age and BEGAIN methylation was identified, suggesting a decrease in BEGAIN methylation in sperm as paternal age increases. The sex-specific impact of paternal age on BEGAIN methylation was observed, with a significant negative correlation in male offspring but not in female offspring.

Regarding chronological age, a significant negative correlation with BEGAIN methylation was found in males but not in females, indicating a potential sex-specific age-related change in BEGAIN methylation.

The study also explored the association between BEGAIN methylation and Autism Spectrum Disorder (ASD). Individuals with ASD were found to have significantly lower levels of BEGAIN methylation compared to age- and sex-matched controls, suggesting a potential involvement of BEGAIN methylation in the development of ASD.

Furthermore, the researchers identified a genetic variant, SNP rs7141087, associated with BEGAIN methylation. The CC genotype of this SNP was linked to lower levels of BEGAIN methylation compared to the TT genotype, potentially contributing to observed differences in BEGAIN methylation between individuals with ASD and controls.

“Individuals with CC genotype of SNP rs7141087 which show a 6% lower methylation than the TT genotype are significantly more frequent in our ASD group than in controls. This could be due to an association of the C allele with autism.”

Conclusions & Future Research

In conclusion, this research provides valuable insights into the effects of paternal and chronological age on BEGAIN methylation and its potential role in ASD. The findings suggest that paternal age and chronological age can influence BEGAIN methylation, and these changes may be associated with an increased risk of ASD. Further research is needed to fully understand the mechanisms underlying these associations and their implications for the development of ASD.

“The male-specific hypomethylation of the BEGAIN promoter in blood, and by extrapolation other somatic tissues is exaggerated in males suffering from autism. Moreover, our results also show a paternal age effect on BEGAIN methylation in sperm and the male offspring (FCB). […] However, the functional implications of small age-associated methylation changes in BEGAIN in a multifactorial disease model remain to be elucidated.”

Click here to read the full study published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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How a Receptor Boosts WNT Signals in Pancreatic Cancer

In this new study, researchers revealed a novel role for LGR6 in enhancing WNT signals in pancreatic cancer. 

Pancreatic cancer is one of the deadliest forms of cancer, with a very low survival rate and limited treatment options. Understanding the molecular mechanisms that drive the development and progression of this disease is crucial for finding new ways to prevent and treat it. One of the key players in pancreatic cancer is the WNT signaling pathway, which regulates many aspects of cell growth, differentiation and survival. WNT signaling is often dysregulated in pancreatic cancer, leading to uncontrolled cell proliferation, invasion and resistance to therapy.

“The canonical WNT pathway is reportedly an essential protagonist in organ development as well as oncogenesis in multiple cancers.”

How does WNT signaling become so powerful in pancreatic cancer cells? In a new study, researchers Jing Wang, Dominik T. Koch, Felix O. Hofmann, Daniel Härtwig, Iris Beirith, Klaus Peter Janssen, Alexandr V. Bazhin, Hanno Niess, Jens Werner, Bernhard W. Renz, and Matthias Ilmer from Ludwig-Maximilians-University, University of Science and Technology of China, Technical University of Munich, and German Cancer Consortium revealed a novel role for a receptor called LGR6 in enhancing WNT signals in this disease. Their research paper was published on September 27, 2023, in Aging’s Volume 15, Issue 20, entitled, “WNT enhancing signals in pancreatic cancer are transmitted by LGR6.”

The Study

LGR6 is a member of the leucine-rich repeat-containing G-protein-coupled receptor (LGR) family, which can bind to proteins called R-spondins (RSPOs). RSPOs are known to potentiate WNT signaling by preventing the degradation of WNT receptors and co-receptors on the cell surface. The authors of this study note that LGR5 has previously been described as a WNT target gene as well as a marker of cancer stem cells. In this study, the team aimed to determine whether its homologue LGR6 incorporates similar functional aspects in pancreatic ductal adenocarcinoma (PDAC).

“In this work, we aimed to decipher the functions of LGR6 in WNT signaling of PDAC, apart from its assumed assignment as a receptor to RSPO. Taken into account the connections between WNT signaling and EMT, we further hypothesized a likely interplay of LGR6 and EMT.”

The researchers found that LGR6 is differentially expressed in various pancreatic cancer cell lines, depending on their phenotype and WNT activation status. Cell lines that have a more epithelial-like appearance and are more sensitive to WNT signals tend to express higher levels of LGR6 than cell lines that have a more mesenchymal-like appearance and are less responsive to WNT signals. Moreover, the researchers showed that adding RSPOs to the culture medium increased LGR6 expression in the epithelial-like cell lines, suggesting that there is a positive feedback loop between LGR6 and WNT signaling.

To investigate the functional role of LGR6 in pancreatic cancer, the researchers used small interfering RNAs (siRNAs) to knock down its expression in two epithelial-like cell lines. They found that reducing LGR6 levels decreased the activation of WNT signaling, as measured by the expression of WNT target genes and the accumulation of β-catenin, a key mediator of WNT signals. It is important to note that β-catenin is also a key mediator of epithelial–mesenchymal transition (EMT) — a process by which epithelial cells disconnect from each other and transdifferentiate into mesenchymal cells. Furthermore, the researchers observed that knocking down LGR6 impaired the ability of PDAC cells to form colonies in soft agar, a measure of their tumorigenic potential. It also reduced their capacity to form spheres in suspension, a measure of their stemness or self-renewal ability.

“Taken together, we present new evidence in PDAC that LGR6 might be a novel WNT target gene in this tumor. LGR6 seems to be involved in EMT and cancer stemness.”

Conclusions

This study sheds new light on the molecular mechanisms that modulate WNT signaling in pancreatic cancer and reveals a novel role for LGR6 as a WNT enhancer. Their results suggest that LGR6 is an important regulator of WNT signaling and stemness in pancreatic cancer cells, especially those with an epithelial phenotype. The authors propose that LGR6 may act as a switch that amplifies WNT signals in response to RSPOs, thereby enhancing the malignant properties of pancreatic cancer cells. They also speculate that LGR6 may have potential value for treatment stratification of pancreatic cancer patients, as its expression may indicate the responsiveness of tumors to therapies targeting WNT signaling.

“This knowledge could be applicable for detection and treatment of special subsets of pancreatic cancer cells. Further research is still needed to dissect the exact mechanisms under physiological as well as pathological conditions of benign and cancerous pancreatic cells.”

Click here to read the full study published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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Rapamycin’s Therapeutic Potential in Treating Werner Syndrome

In this new study, researchers from Japan investigated the molecular mechanisms of subcutaneous fat dysfunction in Werner syndrome.

Between 1904 and 2008, researchers found that approximately 75% of patients with Werner syndrome (WS) worldwide were of Japanese descent. WS is a rare genetic disorder that causes premature aging and increases the risk of various age-related diseases, such as diabetes, cardiovascular disease and cancer. One of the hallmarks of WS is the loss of subcutaneous fat, which is the layer of fat under the skin that helps regulate body temperature and store energy. Subcutaneous fat loss leads to severe insulin resistance, which means that the body cannot use glucose effectively and has high blood sugar levels. But what causes subcutaneous fat loss in WS? And how does it affect the metabolism and health of WS patients? 

In a new study, researchers Daisuke Sawada, Hisaya Kato, Hiyori Kaneko, Daisuke Kinoshita, Shinichiro Funayama, Takuya Minamizuka, Atsushi Takasaki, Katsushi Igarashi, Masaya Koshizaka, Aki Takada-Watanabe, Rito Nakamura, Kazuto Aono, Ayano Yamaguchi, Naoya Teramoto, Yukari Maeda, Tomohiro Ohno, Aiko Hayashi, Kana Ide, Shintaro Ide, Mayumi Shoji, Takumi Kitamoto, Yusuke Endo, Hideyuki Ogata, Yoshitaka Kubota, Nobuyuki Mitsukawa, Atsushi Iwama, Yasuo Ouchi, Naoya Takayama, Koji Eto, Katsunori Fujii, Tomozumi Takatani, Tadashi Shiohama, Hiromichi Hamada, Yoshiro Maezawa, and Koutaro Yokote from Chiba University Graduate School of Medicine, Chiba University Hospital, Kazusa DNA Research Institute, The University of Tokyo, Kyoto University, and International University of Welfare and Health School of Medicine aimed to shed light on these questions by investigating the molecular mechanisms of subcutaneous fat dysfunction in WS. On October 3, 2023, their research paper was published in Aging’s Volume 15, Issue 19, entitled, “Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome.”

“[…] research on WS is important as it can provide insights into the pathogenesis and development of treatments not only for WS but also for general age-related diseases [5].”

The Study

The researchers analyzed subcutaneous fat samples from four Japanese patients with WS and compared them with samples from healthy individuals. They found that WS subcutaneous fat cells showed signs of cellular senescence, which is a state of irreversible growth arrest that occurs when cells are exposed to stress or damage. Senescent cells secrete inflammatory molecules that can harm neighboring cells and tissues, known as senescence-associated secretory phenotype, or SASP.

The study also revealed that WS subcutaneous fat cells had impaired adipogenesis, which is the ability to differentiate into mature fat cells that can store lipids and secrete hormones. This was associated with reduced expression of genes involved in insulin signaling and lipid metabolism, such as IRS1, PI3K, AKT, and SREBP1. Moreover, the researchers found that rapamycin, a drug that inhibits a protein called mTOR that regulates cell growth and metabolism, could partially restore insulin signaling and adipogenesis in WS subcutaneous fat cells.

“These results suggest that rapamycin rescues cellular senescence and insulin resistance in WSVF [WS subcutaneous adipose tissues], and extends the lifespan of the WS model in vivo.”

Their findings suggest that senescence-associated inflammation and inhibition of adipogenesis play a role in subcutaneous fat reduction and dysfunction in WS, which may contribute to insulin resistance and metabolic disorders. This study also provides evidence that targeting mTOR with rapamycin or other drugs may have therapeutic potential for improving subcutaneous fat function and metabolic health in WS patients.

Conclusions

This study is one of the first to explore the molecular mechanisms of subcutaneous fat dysfunction in WS using human samples. It adds to the growing body of research on the role of senescence and inflammation in aging and age-related diseases. It also highlights the importance of subcutaneous fat as a key metabolic organ that affects not only body shape but also systemic health.

“Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans. To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.”

Click here to read the full study published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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How Cognitive Reserve Can Help You Sleep Better and Think Sharper

In a new study, researchers investigated the association between sleep, cognitive reserve and cognition in older adults.

Sleep is vital for our health and well-being, but as we age, we tend to experience less and less of it. In particular, we lose some of the deep sleep stages, known as slow wave sleep (SWS), that are crucial for memory consolidation and brain maintenance. This can affect cognitive performance and increase our risk of developing dementia.

Not everyone is equally vulnerable to the negative effects of poor sleep quality. Some people seem to be more resilient and able to cope with less SWS without compromising their mental abilities. What makes them different? One possible factor is cognitive reserve (CR).

CR is a concept that refers to the brain’s ability to adapt and compensate for age-related changes or brain damage. It is influenced by various aspects of our life experiences, such as education, occupation, leisure activities, social interactions, and mental stimulation. People with higher CR are thought to have more efficient brain networks, more cognitive strategies, and more brain reserve (i.e., more neurons and connections) that can buffer the impact of aging or pathology on cognition.

In a new study, researchers Valentin Ourry, Stéphane Rehel, Claire André, Alison Mary, Léo Paly, Marion Delarue, Florence Requier, Anne Hendy, Fabienne Collette, Natalie L. Marchant, Francesca Felisatti, Cassandre Palix, Denis Vivien, Vincent de la Sayette, Gaël Chételat, Julie Gonneaud, and Géraldine Rauchs from Normandie University, UNI – ULB Neuroscience Institute, University of Liege, University College London, and CHU de Caen aimed to identify individuals in whom sleep disturbances might have greater behavioral consequences. On September 28, 2023, their research paper was published in Aging’s Volume 15, Issue 18, entitled, “Effect of cognitive reserve on the association between slow wave sleep and cognition in community-dwelling older adults.”

The Study

The researchers investigated whether CR could modulate the association between SWS and cognition in older adults. The researchers recruited 135 cognitively intact older adults (mean age: 69.4 years) from the Age-Well randomized controlled trial and measured their sleep quality using polysomnography — a technique that records brain waves, eye movements, muscle activity, and other physiological signals during sleep. They also assessed their cognitive performance using neuropsychological tests that evaluated executive function (i.e., the ability to plan, organize, monitor, and control one’s behavior) and episodic memory (i.e., the ability to remember personal events and experiences).

To estimate CR, the researchers used two measures of cognitive engagement throughout life: a questionnaire that asked about the frequency and diversity of participation in various activities (such as reading, playing games, learning languages, etc.) in different age periods; and a composite score based on the highest level of education attained, the complexity of the main occupation held, and the current cognitive activity level.

The results showed that SWS was positively associated with episodic memory performance, meaning that participants who had more SWS tended to have better memory scores. However, this association was not observed for executive function performance. CR proxies modulated the associations between SWS and both executive and episodic memory performance. Specifically, participants with higher CR were able to maintain cognitive performance despite low amounts of SWS, whereas participants with lower CR showed a steeper decline in performance as SWS decreased.

“This study provides the first evidence that CR may protect against the deleterious effects of age-related sleep changes on cognition.”

Conclusions

The study suggests that engaging in cognitively stimulating activities throughout life may enhance one’s ability to cope with less SWS without compromising one’s mental abilities. It also highlights the importance of considering individual differences in CR when evaluating the impact of sleep quality on cognition in older adults.

The authors were forthcoming about limitations of their study, such as the cross-sectional design that does not allow causal inferences, the relatively small sample size that limits the generalizability of the findings, and the use of proxy measures that may not capture all aspects of CR. They also point out some directions for future research, such as exploring the underlying mechanisms of how CR influences sleep-cognition relationships, examining whether CR can also modulate the effects of other sleep parameters (such as sleep duration or fragmentation) on cognition, and investigating whether interventions that target sleep quality or CR can improve cognitive outcomes in older adults.

In conclusion, this study suggests that CR may be an important factor that can help us sleep better and think sharper as we age. It also encourages us to keep our brains active and challenged throughout our lives, as this may benefit not only our cognitive functioning but also our sleep quality.

“These findings are important to understand the factors promoting successful aging and suggest that the deleterious impact of sleep disturbances could be counteracted by an enriched lifestyle. This will help to design non-pharmacological interventions to promote successful aging and counter age-related sleep changes.”

Click here to read the full study published in Aging.

Interested in reading more about cognitive reserve and aging? Click here.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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The Role of R-loops in Neuronal Aging

In a new editorial, researcher Hana Hall discusses the role of R-loops in neuronal aging and neurodegeneration. 

R-loops are structures that form when the nascent RNA hybridizes with the template DNA strand, displacing the non-template strand. In other words, R-loops are like temporary tangles in our DNA where a new RNA molecule forms by copying one of the DNA strands and pushes aside the other DNA strand. Nascent RNA refers to the newly synthesized RNA molecule that is produced during the process of transcription. In addition to transcription, R-loops are involved in various biological processes, such as splicing, DNA repair and chromatin remodeling. However, when R-loop homeostasis is disrupted, they can also cause transcriptional impairment, genome instability and cellular dysfunction.

“R-loops have been shown and studied in a wide range of organisms and while they have important regulatory roles, persistent R-loops can be detrimental to cell function and survival, having been closely linked to both gene expression dysregulation and increased genome instability.”

In a new editorial paper, researcher Hana Hall from the Purdue Institute for Integrative Neuroscience at Purdue University discusses the role of R-loops in neuronal aging and neurodegeneration. On September 13, 2023, her editorial was published in Aging’s Volume 15, Issue 17, and entitled, “R-loops in neuronal aging.” Hall summarizes her recent study and the current knowledge on how R-loop levels change during aging, how they affect gene expression and neuronal function, and how they are regulated by different factors.

“In our recent study, we demonstrated that R-loops accumulate in fly PR [photoreceptor] neurons by middle age and significantly increase into late-life stages [5].”

The Editorial

According to Hall, R-loop levels increase with age in different organisms and tissues, including neurons. This could be due to several reasons, such as reduced expression or activity of R-loop resolving enzymes (e.g., Top3β, RNase H1), increased transcriptional activity or stress, or impaired DNA repair mechanisms. Hall also highlighted that R-loop accumulation is associated with decreased expression of long and highly expressed genes, which are enriched for neuronal functions. This could lead to impaired neuronal activity and communication, as well as increased vulnerability to neurodegenerative diseases.

“Our study provides first evidence of R-loop accumulation in aging neurons and a contributing role in loss of neuronal function during aging.”

Hall further discussed how R-loop homeostasis is modulated by various factors, such as chromatin structure, epigenetic modifications, RNA-binding proteins, and non-coding RNAs. She also mentioned some potential therapeutic strategies to restore R-loop balance in aging neurons, such as overexpressing or delivering R-loop resolving enzymes, modulating chromatin accessibility or targeting specific R-loop forming genes.

Conclusions

Hall concluded that R-loops are important players in neuronal aging and neurodegeneration, and that more studies are needed to understand their molecular mechanisms and functional consequences. She also suggested that R-loop mapping could be used as a biomarker to monitor neuronal health and disease progression. This editorial provides a comprehensive overview of the current knowledge of R-loops in neuronal aging, and highlights the challenges and opportunities for future research. 

“Undoubtedly, R-loops are at the crossroads of several hallmarks of aging, namely transcriptional stress, genome instability, and chronic immune response. Targeting R-loop levels thus may help restore these pathways to a normal/healthy state and slow down or prevent the onset of age-dependent neurodegenerative diseases.”

Click here to read the full editorial published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact media@impactjournals.com.

The Impact of Age on Melanoma: Insights from Recent Research

In a new editorial, researchers delve into the intricate dynamics of melanoma and aim to illuminate differences in age-related incidence, prognosis and treatment.

In the realm of cancer research, one persistent trend has emerged — the incidence of invasive melanoma rises steadily with advancing age. While this insidious disease remains rare in children and adolescents, it progressively asserts its presence as individuals grow older. The connection between age and melanoma incidence persists around the world, albeit with varying rates in different countries. 

Australia has the highest melanoma rates in the world. According to the Melanoma Institute Australia, every 30 minutes an Australian is diagnosed with melanoma and every 6 hours an Australian dies from it. Thankfully, research is making a difference. In the last decade, the 5-year overall survival rate for advanced melanoma has increased from less than 10% to more than 50%. In 2011, melanoma was Australia’s 7th most deadly cancer. In 2021, melanoma was Australia’s 11th most deadly cancer.

Figure 1. Melanoma incidence (A) and mortality (B) according to age [2].

In a new editorial paper, researchers John F. Thompson and Gabrielle J. Williams from the Melanoma Institute Australia at The University of Sydney discuss the intricacies of how age influences different varieties of melanoma incidence, prognosis and treatment. On August 17, 2023, their editorial was published in Aging’s Volume 15, Issue 16, entitled, “The effect of age on melanoma incidence and prognosis.”

Understanding Melanoma Subtypes

The researchers point out that while invasive melanoma is at the forefront of discussion, non-invasive “melanoma in situ” (MIS) follows a similar age-related pattern of increase. MIS, often exemplified by lentigo maligna (LM), results from chronic, accumulated exposure to ultraviolet light. The progression from LM to invasive lentigo maligna melanoma (LMM) occurs at an estimated rate of 3.5% per year, with an average transition period of 28.3 years.

Older patients are more prone to another unique subtype known as desmoplastic melanoma, linked to chronic sun exposure and frequently affects the head or neck. While desmoplastic melanomas have a somewhat higher local recurrence rate, the majority of invasive melanomas in elderly patients exhibit features associated with poorer prognosis, including ulceration, higher mitotic rates and increased Breslow thickness.

Melanoma Biopsies & Treatment Options

Patients with high-risk primary melanomas are often recommended for a sentinel lymph node biopsy (SLNB) to assess the presence of metastatic melanoma cells in regional lymph nodes—a pivotal prognostic factor. Strikingly, the likelihood of a positive SLNB result decreases with age. However, as age advances, the risk of death due to melanoma’s spread to distant sites increases, leaving researchers grappling with the mysteries of why these phenomena occur.

Current treatments for SLN-positive melanoma patients include immunotherapy and targeted therapy. Immunotherapy agents like ipilimumab, pembrolizumab and nivolumab have shown promise in treating melanoma. While initial clinical trials excluded the very young and elderly, subsequent non-randomized studies have revealed that these agents are similarly effective in older patients, with comparable adverse event profiles. However, the efficacy of these therapies in children and adolescents remains uncertain.

Targeted therapies focusing on BRAF mutations, including vemurafenib and dabrafenib, have been employed, particularly in younger patients who exhibit a higher prevalence of BRAF positivity. Response rates are significant but often followed by resistance. Interestingly, these therapies appear to exhibit similar efficacy and safety profiles in older patients, offering a glimmer of hope for this demographic.

In older melanoma patients with brain metastases, radiation therapy has historically played a crucial role, offering alternatives to surgical excision. Studies have revealed that both whole-brain radiotherapy and stereotactic radiotherapy are equally effective in patients aged 70-90 as in younger groups. With the advent of immunotherapy and targeted therapies, combining localized radiation with systemic treatment is becoming an option, particularly in older patients, offering the potential for similar benefits as seen in younger cohorts.

Conclusions & Future Directions

The data presented in this editorial underscore a stark reality — melanoma’s impact escalates with age. Patterns of the disease differ significantly in older age groups, with increasing rates of metastasis and death. However, standard forms of melanoma management, including surgery, radiation therapy and newer systemic therapies, have proven to be as effective and safe in older patients as in their younger counterparts. This knowledge serves as a beacon of hope, offering solace and potential avenues for treatment in the face of this disease.

In closing, the critical role of research and continued investigation cannot be overstated. Further exploration of age-related nuances in melanoma will undoubtedly uncover new insights and lead to more tailored and effective treatments for all patients, regardless of their age.

Click here to read the full editorial published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact media@impactjournals.com.

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