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First Evidence of a Pan-tissue Decline in Stemness During Human Aging

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In this new study, researchers provide the first evidence of a pan-tissue decrease of stemness during human aging.

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Aging is still shrouded in proverbial darkness. But, some researchers hypothesize that aging may be linked to stem cell exhaustion. Stemness, the ability of a cell to differentiate into various cell types, is an essential characteristic defining the functionality of stem cells. It has been observed that stem cells seem to diminish with age, although the precise role of stem cells in human aging remains to be elucidated. 

“Among the biological pathways associated with aging, we can highlight stem cell exhaustion, which argues that during normal aging, the decrease in the number or activity of these cells contributes to physiological dysfunction in aged tissues [4].”

In a new study, researchers Gabriel Arantes dos Santos, Gustavo Daniel Vega Magdaleno and João Pedro de Magalhães from the Universidade de Sao Paulo, University of Birmingham and the University of Liverpool applied a machine learning method to detect stemness signatures from transcriptome data of healthy human tissues. Their research paper was published on April 4, 2024, and chosen as the cover of Aging’s Volume 16, Issue 7, entitled, “Evidence of a pan-tissue decline in stemness during human aging.”

The Study

In this study, the researchers delve into the intricate relationship between aging and stemness, offering vital insights into this complex interplay. The researchers conducted an in-depth analysis of healthy human tissue samples, assigning “stemness scores” to track the stemness levels across different age groups.

“In this context, detecting stemness-associated expression signatures is a promising strategy for studying stem cell biology.”

This research is the first to provide evidence of a pan-tissue decline in stemness during human aging. It is an important step forward in understanding the cellular mechanisms involved in the aging process and their potential implications for human health.

Methodology & Data Sources

The researchers used the RNA-Seq-based gene expression data from human tissues, downloaded from the Genomics of Ageing and Rejuvenation Lab’s Genomics of Ageing (GTEx) portal. This comprehensive dataset included over 17,000 healthy human tissue samples, spanning an age range of 20 to 79 years.

A machine learning methodology, originally developed by Malta et al., was applied to the GTEx transcriptome data to assign stemness scores to all samples. This advanced machine learning model was trained on stem cell classes and their differentiated progenitors, enabling the researchers to detect stemness signatures from the transcriptome data of healthy human tissues.

Key Findings

The analysis revealed a significant negative correlation between the subject’s age and stemness score in approximately 60% of the studied tissues. Interestingly, the only exception was the uterus, which exhibited increased stemness with age. This finding is particularly noteworthy, as it provides the first evidence of a pan-tissue decline in stemness during human aging. It supports the hypothesis that stem cell deterioration may contribute to the aging process.

The researchers also observed interesting correlations between stemness and other cellular processes. They found that stemness was positively correlated with cell proliferation. However, this relationship was not universal, with some tissues showing exceptions.

In contrast, when they examined the association between stemness and cellular senescence, a negative correlation was observed across the board. This finding suggests that although senescent cells and stem cells are not technically opposite states, they behave in opposite ways at the transcriptomic level within a living organism.

Implications & Future Directions

The findings of this study have far-reaching implications for our understanding of the aging process and its cellular underpinnings. By providing the first evidence of a pan-tissue decline in stemness during human aging, the study adds significant weight to the notion that stem cell deterioration may contribute to human aging.

However, many questions remain. For instance, it is not yet clear whether the loss of stemness contributes to aging or is a consequence of it. Moreover, it is uncertain whether the decline in stemness is due to a direct reduction in the stem cell pool or refers to intrinsic changes in different cells within the tissue.

Further research is needed to address these questions, and more robust studies are required to draw more assertive conclusions. It is also crucial to determine which factors drive these changes and which patterns and genes are associated with this process. This will be pivotal in advancing our understanding of stemness aging and its potential implications for human health.

“In conclusion, we provide the first evidence of a pan-tissue decrease of stemness during human aging and report an association between stemness and cell proliferation and senescence. This study also assigned a stemness score to more than 17,000 human samples, and these data can be useful for the scientific community for further studies.”

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

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Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. 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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Overcoming Missing Data in the Swedish National Study on Aging

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In this new study, researchers compared three multiple imputation strategies for overcoming the missing discrete variable of gait speed in the Swedish National Study on Aging and Care (SNAC).

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Missing data in aging studies, especially in the assessment of gait speed (the time it takes individuals to cover a set distance), presents a significant challenge. The elderly are more prone to health and functional issues, which often interfere with data collection efforts. Given that gait speed is a key indicator of functional status and overall health in older individuals, ensuring its availability and accurate measurement is essential for the integrity of aging research.

In a new study, researchers Robert Thiesmeier, Ahmad Abbadi, Debora Rizzuto, Amaia Calderón-Larrañaga, Scott M. Hofer, and Nicola Orsini from Karolinska Institutet, Stockholm University, Stockholm Gerontology Research Center, and Oregon Health and Science University address the systematic challenge of missing gait speed data in aging research and explore the application of multiple imputation (MI), a statistical technique that has emerged as a constructive approach to handle such gaps in data. The team critically examined the implementation strategies, methodologies, and the impact that these missing variables could have on the outcomes of aging studies, thereby offering a framework to manage and interpret incomplete datasets in aging research. On February 14, 2024, their research paper was published in Aging’s Volume 16, Issue 4, entitled, “Multiple imputation of systematically missing data on gait speed in the Swedish National Study on Aging and Care.”

“[…] this study aims to investigate and assess the performance of different MI strategies specifically targeting the systematically missing discrete variable of gait speed in the SNAC [Swedish National Study on Aging and Care] IPDMA [individual participant data meta-analyses] with only four large cohort studies.”

Setting the Context

Before delving into the specifics of the study, it’s crucial to comprehend the broader context. Aging, as a biological process, presents numerous challenges, particularly in healthcare. Addressing these challenges requires comprehensive data to inform clinical diagnosis and prognosis. The Swedish National Study on Aging and Care (SNAC) is one such initiative that aims to provide a holistic view of aging and elderly data.

SNAC was launched in 2001 as an ongoing longitudinal cohort study based on samples of the Swedish elderly population. The study comprises four sites: Kungsholmen, Skåne, Nordanstig, and Blekinge. Each site collects data on health determinants, disease outcomes, functional capacity, and social conditions. SNAC’s diverse data collection has facilitated the development of an innovative Health Assessment Tool integrating indicators of both clinical and functional health in a population aged 60+ years.

SNAC, like any extensive study, faces the issue of missing data. One variable, gait speed, is systematically absent in one study site, Blekinge. This absence poses a significant challenge for researchers. They must decide between using complete data from only three studies, risking information loss and potential bias in combined estimates, or employing multiple imputation (MI) methods to estimate missing values based on observed data.

What is Multiple Imputation?

Gait speed, or the speed at which a person walks, is a simple but powerful indicator of health and functional status in older adults. It can predict the risk of mortality, disability, cognitive decline, and institutionalization. However, measuring gait speed is not always feasible in large-scale epidemiological studies, especially when participants are frail, have mobility limitations, or live in remote areas. This can result in missing data on gait speed, which can bias the estimates of its association with health outcomes and reduce the statistical power of the analyses.

One way to handle missing data on gait speed is to use multiple imputation, a statistical technique that replaces each missing value with a set of plausible values that reflect the uncertainty about the true value. Multiple imputation can reduce bias and increase precision compared to excluding cases with missing data or using a single imputation method. However, there are different ways to perform multiple imputation, and some may be more suitable than others depending on the type and pattern of missing data.

The Study

In the current study, the researchers compared three multiple imputation strategies for dealing with systematically missing data on gait speed in the SNAC. The SNAC consists of four prospective cohort studies that measured gait speed at baseline and follow-up, except for one study that did not measure gait speed at all. The authors simulated 1000 individual participant data meta-analyses (IPDMA) based on the characteristics of the SNAC and evaluated the performance of three multiple imputation strategies: fully conditional specification (FCS), multivariate normal (MVN), and conditional quantile imputation (CQI).

The FCS method imputes each variable separately by using regression models that depend on the other variables in the dataset. The MVN method assumes that the data follow a multivariate normal distribution and imputes all variables simultaneously by using an expectation-maximization algorithm. The CQI method imputes discrete variables by using quantile regression models that preserve the distribution of the original data.

The authors analyzed the imputed datasets with a two-stage common-effect multivariable logistic model that estimated the effect of three levels of gait speed (<0.8 m/s, 0.8-1.2 m/s, >1.2 m/s) on 5-years mortality. They found that all three imputation methods performed relatively well in terms of bias and coverage of the confidence intervals. However, the CQI method showed the smallest bias and the best coverage for both low and high levels of gait speed. The FCS and MVN methods tended to overestimate the effect of low gait speed and underestimate the effect of high gait speed on mortality.

Conclusions

The authors concluded that multiple imputation can be a useful tool for dealing with systematically missing data on gait speed in IPDMA based on the SNAC. They recommended the CQI method as the preferred approach for imputing discrete variables such as gait speed, as it preserves the original distribution and avoids unrealistic values. They also highlighted the importance of reporting the details of the multiple imputation procedure and checking the plausibility of the imputed values.

This study provides valuable insights for researchers who face similar challenges with missing data on gait speed or other discrete variables in aging research. By using appropriate multiple imputation methods, they can improve the validity and reliability of their results and avoid losing valuable information.

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

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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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Senescence-Related TME Genes as Key Prognostic Predictors in HNSCC

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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. 

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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.

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

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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).

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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.

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

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

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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.

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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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Rapamycin’s Therapeutic Potential in Treating Werner Syndrome

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

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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.

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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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How Cognitive Reserve Can Help You Sleep Better and Think Sharper

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

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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.

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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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The Role of R-loops in Neuronal Aging

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

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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.

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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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Dry Eyes? It May be Immune Infiltration in Aging Lacrimal Glands

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In a new editorial, researchers from Baylor College of Medicine artfully discuss the immune system’s role in dry eye disease. 

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The lacrimal gland, found in the upper outer part of the eye’s hollow area, is an important gland that makes tears to protect the eye from infections. It’s split into two parts: one near the inside of the eyelid that can be seen when the eyelid is flipped, and another part with ducts lower in the eye that connects to its counterpart. In their fully functioning status, these ducts release fluid onto the surface of the eye. As humans age (especially women), the lacrimal gland gradually becomes infiltrated by aberrant immune cells and can ultimately lead to an uncomfortable condition known as dry eye disease.

“Burning and redness in the eyes, grittiness and blurry vision make life miserable and currently, eye drops with a variety of lubricant components and in the most severe cases, immunosuppressors, are the only therapies approved for this disease.”

In a well-written new editorial paper, researchers Claudia M. Trujillo-Vargas and Cintia S. de Paiva from the Department of Ophthalmology at Baylor College of Medicine artfully discuss their recent studies which shed light on the immune system’s role in dry eye disease. On August 11, 2023, their editorial was published in Aging’s Volume 15, Issue 15, entitled, “Our search of immune invaders in the aged lacrimal gland.”

Editorial Summary

The authors write that their research group has been dedicated to investigating the changes that occur in the lacrimal gland due to aging and focus on immunopathological alterations. Due to limited human samples, their studies have centered on understanding the infiltration of lymphocytes, specifically B and T cells, in aged mice’s lacrimal glands. This infiltration has been linked to increased dysfunction of the ocular surface. 

“In the search of mechanisms that can counteract the effects of the overwhelming immune infiltration, we started characterizing one of the main players of immune tolerance, the thymic-derived T regulatory cells (Tregs).”

The researchers and their team have a particular interest in thymic-derived T regulatory cells (Tregs), which play a key role in immune tolerance. Paradoxically, in the aged glands, these Tregs, while exhibiting markers for their suppressive function, display heightened differentiation, infiltrate the tissue, produce inflammatory cytokines, and demonstrate impaired suppressive capabilities. When transferred to immunodeficient recipients, these dysfunctional Tregs replicate lacrimal gland pathology. 

Aged lacrimal glands contain highly differentiated CD4+ T cells of the Th1 and Th17 phenotypes, which exhibit exhaustion and immunopathological features. This environment hampers Tregs’ ability to suppress immune responses. There’s also an increase in naïve CD4+ T cells and IgD+ B cells, suggesting a unique environment for the recruitment of inexperienced immune cells in the gland.

Ectopic lymphoid structures, resembling those found in aged tissues, are observed in the lacrimal gland, potentially contributing to immune dysregulation. Despite the concept of immune cells being unwelcome invaders, the lacrimal gland relies on immune cell influx for surveillance purposes, as it is highly vascularized. Nonetheless, with age, immune cell infiltration intensifies, accompanied by fibrosis, duct issues and gland atrophy. Interestingly, antigen-presenting cells diminish, adding to the peculiar immune environment.

In their running analogy to the movie “Men in Black,” the researchers explain that they are seeking effective therapies, akin to the “noisy crickets,” to combat this pathological immune infiltration. They’re investigating differentially expressed genes in the aged gland, focusing on Tregs expressing Il1r2, CD81 and Tbx21, and B cells showing increased CD79a/b expression. The researchers are also exploring the gut microbiota’s role in ocular barrier disruption and dry eye disease in mice. This could lead to more cost-effective microbial treatments for dry eye disease in humans. However, the effectiveness of these therapies in impeding lymphocyte infiltration in aged lacrimal glands remains uncertain.

Conclusions & Future Directions

In conclusion, their editorial provides valuable insights into the role of the lacrimal gland in the immune system and how it could be used to develop new treatments for dry eyes and other age-related eye diseases. The authors’ research has shown that aged lacrimal glands are infiltrated not only by highly differentiated B but also T cells. This landscape is associated with increased ocular surface dysfunction. The authors suggest that this information could be used to develop new therapies for age-related eye diseases.

Considering the rising pollution and screen dependence in the past decade, the researchers predict an increase in severely damaged lacrimal glands in the elderly. This environment could foster the development of ectopic lymphoid structures, potentially leading to a higher prevalence of dry eye disease. As such, interventions will be required to mitigate the immune damage to the lacrimal gland. Ultimately, protecting the lacrimal glands from the consequences of immune dysregulation is a critical goal.

“Unquestionably, more than ‘fancy sunglasses’ would be needed to hinder the ‘carbonizing’ immune damage in the gland. Thus, Yes! We certainly need to protect our lacrimal glands from the scum of our own immune universe!”

Click here to read the full editorial published in Aging.

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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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Navigating the Frailty Factor in Atrial Fibrillation Management

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In a new editorial, researchers discuss the impact of frailty on clinical decision-making in managing patients with atrial fibrillation and the prescription of oral anticoagulants.

Atrial fibrillation (AF) is a type of heart arrhythmia that occurs when the ​​heart’s electrical signals become irregular. This condition can increase the risk of stroke and heart failure, and becomes more common in older adults. Frailty is another condition that coincides with aging. Frailty encompasses an accumulation of deficits and can be defined as decreased physical function and resilience. For a significant proportion of the elderly population, both of these conditions coexist. This convergence can lead to additional health issues and further complicate the clinical landscape for aging individuals. 

“The impact of frailty on outcomes has not been previously well characterized in populations with AF.”

Studies on frailty and its overall impact on patients with AF are needed. In a new editorial paper, researchers Stephanie L. Harrison, Søren P. Johnsen and Gregory Y.H. Lip from Liverpool John Moores University and Liverpool Heart and Chest Hospital discuss some of the existing studies assessing frailty and AF in terms of patient outcomes and clinical decision-making. The researchers also discuss recommendations for clinical management of AF and frailty patients and include suggestions for future studies. On July 19, 2023, their editorial was published in Aging’s Volume 15, Issue 14, entitled, “The impact of frailty on the management of atrial fibrillation.”

Oral Anticoagulants for AF With Frailty: Yay or Nay?

Oral anticoagulants (OACs) are often prescribed to AF patients, as OACs aid in reducing blood clots and the risk of stroke. However, frailty patients are more susceptible to falls and therefore, more susceptible to bleeding risk. The prevention of blood clots is less than ideal for wound healing and can lead to impaired tissue repair, increased risk of infection and prolonged recovery times. Has frailty status impacted clinical decision-making when it comes to the prescription of OACs for AF patients?

“The impact of frailty on clinical decision making for managing patients with AF such as the prescription of oral anticoagulants (OACs) is unclear.”

In an effort to begin answering this question, the authors of this editorial reviewed a number of studies on frailty and AF. Some cross-sectional analyses revealed a significant association between frailty status and the prescription of OACs, while other studies found no such association. The authors explain that these dueling results may be due to differences in study populations, the tools/methods used to assess frailty and the timing of when the studies were conducted. The prescription of anticoagulants increased when a new class of OACs was introduced to the market.

Non-vitamin K antagonist oral anticoagulants (NOACs) were first introduced in the early 2010s. They are a class of drugs with significant advantages over traditional OACs, including less off-target effects, more predictable pharmacokinetics and a more targeted mechanism of action — making them a safer option for use in combination with other drugs. Notably, certain NOACs have specific reversal agents available, which can be used to rapidly reverse their anticoagulant effect in case of emergency. International guidelines recommended their use as a first-line treatment to reduce the risk of stroke in AF patients.

“Frailty alone should not be reason to withhold oral anticoagulation in patients with AF. In patients with frailty, the benefits of oral anticoagulation outweigh the small absolute risk of bleeding [6].”

Conclusions & Future Directions

The authors close the editorial by stating that additional research is needed to understand how frailty impacts clinical decision-making for the management of atrial fibrillation. They strongly suggest that frailty not be the sole reason AF patients are not prescribed potentially life-saving oral anticoagulants. There are more sensitive options available today, such as NOACs, that can potentially mitigate the drawbacks of anticoagulants for people with frailty. The authors also emphasize that pre-frailty assessments should be conducted for AF patients in order to reduce treatment risk and optimize the management of this condition.

“Assessment of pre-frailty in patients with AF and the development of strategies to address potentially modifiable components of pre-frailty to reduce the risk of frailty progression could have important implications to optimize care.”

Click here to read the full editorial published in Aging.

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Aging is an open-access, peer-reviewed journal that has been publishing high-impact papers in all fields of aging research since 2009. These 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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