PandaOmics Identifies Dual-Targets of Aging and Age-Related Diseases

Researchers used PandaOmics software to identify potential drug targets that could treat both aging and age-related diseases.

Researchers used PandaOmics software to identify potential drug targets that could treat both aging and age-related diseases.

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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What if drugs designed to treat conditions such as diabetes, osteoporosis and rheumatoid arthritis could at the same time provide patients with anti-aging benefits? On March 29, 2022, researchers—from Insilico MedicineUniversity of ChicagoGeorge Mason UniversityUniversity of Liverpool, and Buck Institute for Research on Aging—released a new study on the cover of Aging (Aging-US) Volume 14, Issue 6, about Insilico’s next-generation artificial intelligence (AI)-powered discovery software, called the PandaOmics platform. Their trending research paper is entitled, “Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine.”

PandaOmics

The PandaOmics platform is a software based on an enormous database of research that is constantly being updated and refined. The database consists of over 1,500 diseases and 10,000 disease subtypes, approximately 1.9 trillion data points derived from over 10 million samples with microarrays, RNA sequencing, proteomes, methylomes, and other data types, 1.3 million drug compounds and biologics, and information embedded from over 40 million text-based sources and documents. This evolving omics database is then used to inform an intricate AI algorithm designed to identify patterns within the data.

The Hallmarks of Aging

While the underlying molecular mechanisms of aging are still technically in debate, researchers have basically agreed upon a consistent series of biochemical changes that have been identified in the aging process, known as the hallmarks of aging. There are nine classic hallmarks of aging, as well as three newer additions, which include: 1) altered intercellular communications, 2) cellular senescence, 3) deregulated nutrient signaling, 4) epigenetic shift, 5) genomic instability, 6) impaired proteostasis, 7) mitochondrial dysfunction, 8) stem cell exhaustion, 9) telomere attrition, 10) inflammation, 11) extracellular matrix stiffness, and 12) retrotransposons. 

Researchers have observed that substantial overlap exists between genes involved in the hallmarks of aging and in age-associated diseases (AADs). The goal of this study was to use the PandaOmics platform and the hallmarks of aging to identify dual-purpose drug targets that can be used to treat both aging and AADs.

“Hence, identifying potential targets that are implicated in multiple age-associated diseases, and also play a role in the basic biology of aging, may have substantial benefits.”

The Study

In this study, the researchers used the PandaOmics platform to generate a list of promising new or traditional aging-associated targets that may be used for drug discovery and repurposing. The team started by investigating genes that are dysregulated in multiple aging-associated diseases, as well as in aging itself. The researchers decided only to analyze 33 diseases. This decision was based on whether or not age is a strong risk factor for the disease’s onset, if there are strong confounding factors and on the availability of public datasets. Cancers and cardiovascular diseases were excluded from this list of selected diseases (this list can be found in the study).

The selected diseases were separated into AADs (n=14) and non-age-associated diseases (NAADs) (n=19). The team then programmed the PandaOmics platform to identify aging-associated patterns by prioritizing the top dysregulated genes in these diseases based on their involvement in the hallmarks of aging. The researchers compared the top-AAD and -NAAD genes and identified 145 overlapping common targets.

Results

“In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging.”

They found that most aging-associated targets were not specific to a single hallmark but were instead involved in multiple hallmarks. The team also found that most of the top targets played a role in the 10) inflammation and 11) extracellular matrix stiffness hallmarks of aging. Four targets were connected to all 12 hallmarks; these targets were AKT1, MTOR, SIRT1, and IGF1. Primary conclusions drawn from the study were that the hallmarks of aging are implicated in multiple AADs and NAADs, and that these hallmarks can be used to identify aging-associated targets for drug discovery and repurposing.

Figure 3. Targets associated with hallmarks of aging.
Figure 3. Targets associated with hallmarks of aging. 

Conclusion

The researchers were forthcoming about limitations in this study. Nevertheless, this exciting research provides valuable insight into the use of AI-powered discovery engines to uncover novel aging-associated targets for drug discovery. The PandaOmics platform is a valuable resource for aging researchers and offers the potential to identify new or traditional targets for the treatment of aging and age-related diseases.

“In conclusion, we successfully established an approach to identify potential dual-purpose targets for aging and AADs, enabling biologists and clinicians to further investigate their therapeutic potential in a cost-saving and time-efficient manner for drug discovery. These promising results underscore the ability of PandaOmics to identify novel targets not only for specific disorders, but across multiple types of diseases.”

Click here to read the full cover paper published in Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Trending With Impact: How Biological Sex Impacts Alzheimer’s Disease

Men and women are disproportionately impacted by Alzheimer’s disease (AD). Researchers investigated AD mice for potential sex differences in synaptic function.

Figure 1. The diagram shows sex-specific alterations in plasticity and memory and the associated changes in amyloid beta (Aβ) pathology and inflammatory response in APP/PS1 mice.
Figure 1. The diagram shows sex-specific alterations in plasticity and memory and the associated changes in amyloid beta (Aβ) pathology and inflammatory response in APP/PS1 mice.

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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As the worldwide elderly population continues to expand, the symptoms of dementia, including Alzheimer’s disease (AD), are simultaneously increasing around the globe. Researchers are driven to investigate new ways to detect and treat AD in earlier stages—before symptoms become more difficult or impossible to overturn. An important piece of data to consider is that dementia is more prevalent among women than among men; dementia affects 8.1 % of women and 5.4% of men. Many AD studies have not used gender/sex as a variable to cross-examine their research findings. This information may be a key factor that leads to developing more efficacious strategies for AD detection and treatment in all patients, and especially in women.

“In the long run, the underrepresentation of female biology in biomedical research will hamper the development of effective drugs with negative consequences on women’s health.”

In a recent editorial paper published on March 12, 2022, by Aging (Aging-US) in Volume 14, Issue 5, researchers from the National University of Singapore discussed the importance of understanding sex differences in Alzheimer’s disease. Their trending editorial paper, entitled, “Sex matters in Alzheimer’s disease?“, was based on results from their previous study published in 2021.

Sex-Specific Synaptic Dysfunction

In AD patients, researchers have observed a loss of function in the sites where nerve cells communicate with each other—in the synapses. Synaptic dysfunction is an early event in AD and can be observed years before other symptoms appear. In the research study being discussed in this editorial, the research team examined differences between the synaptic activity of male and female mice with two mutations associated with early-onset Alzheimer’s disease (APP/PS1).

“To characterize molecular changes in the AD brain that is attributed to sex differences, we performed RNA sequencing and immunohistochemistry of the hippo-campus and showed accelerated pathology, stronger immune response and higher microglial activation in AD female mice compared to males [5].”

Their findings revealed a number of differentially expressed genes and plasticity-related genes were sex-regulated. Plasticity-related genes are important for learning, memory and other cognitive abilities. The study also found that female AD mice had an accelerated Alzheimer’s pathology, stronger immune response and higher microglial activation—all of which contribute to dementia symptoms. These results suggested that sex differences in early-stage synaptic function may have important implications for understanding the higher prevalence of Alzheimer’s disease in women, and the related mechanisms may be potential targets for diagnosis and treatment.

Conclusion

In their editorial paper, the authors acknowledge that, although more research needs to be done on this topic, these findings could lead to new strategies for detecting and treating Alzheimer’s disease. The authors conclude by writing that synaptic dysfunction among males and females with Alzheimer’s disease revealed sex-regulated differentially expressed genes and plasticity-related genes as potential targets for early AD intervention. Overall, sex differences should be considered when developing custom-tailored strategies for early AD detection, prevention and treatment.

​​”Our work, along with others in this field, also emphasises the importance of including biological sex as variable in many research settings, particularly studies exploring aging [7] and how they impact different disease states [8].”

Click here to read the full editorial paper published by Aging (Aging-US).

Click here to read Aging’s Special Collection on Alzheimer’s Disease

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Trending With Impact: Intestinal Balance, Colorectal Cancer and Muc4

Researchers investigated the functional significance of Muc4 in intestinal homeostasis and colorectal cancer progression.

Figure 3. Absence of Muc4 alters other mucins expression.
Figure 3. Absence of Muc4 alters other mucins expression.

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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With age, humans undergo bodily changes which include a decline in organ and tissue function. The average age men and women are diagnosed with colorectal cancer (CRC) is 68 and 72 years old, respectively. Healthy intestinal epithelial cells are usually lined with a sufficient layer of mucus; important components in this mucus layer, called mucins, help to maintain physiological homeostasis. While transmembrane mucin 4 (Muc4) has been found to be overexpressed in pancreatic, ovarian and breast cancers, Muc4 expression is decreased in patients with CRC. The functional role and implications of Muc4 in CRC’s intestinal pathology have not yet been adequately investigated. 

Researchers—from the University of Nebraska Medical CenterBaylor College of MedicineUniversity of California San Diego, and VA San Diego Healthcare System—sought to better understand the role of Muc4 in CRC by developing genetically engineered mouse (GEM) models. Their priority research paper was published as the cover of Aging-US Volume 14, Issue 5, and entitled, “Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer.

“Therefore, to understand the functional significance of MUC4 in intestinal homeostasis and CRC progression, we developed a GEM model by crossing mice carrying a conditional mutation of Apc [adenomatous polyposis coli] gene with colon-specific caudal type homeobox transcription factor 2 (Cdx2)-Cre fused with estrogen receptor.”

The Study

The researchers first conducted an analysis of CRC patients using The Cancer Genome Atlas. They found that CRC patients had decreased Muc4 levels compared to normal patients and that lower Muc4 expression is associated with a worse prognosis in CRC patients. In CRC, the most frequent mutations were found to occur in the Apc gene. Therefore, the researchers tested control mice and two mouse models in this study. The AMC GEM model had an Apc mutation, and Muc4 was knocked out. The AC GEM model was AMC’s contemporary littermate control and had only the Apc mutation—Muc4 was not knocked out. Tamoxifen was then intraperitoneally administered to exert conditional control of gene expression in the mice.

Next, the team conducted mucin staining to characterize goblet cell function. Goblet cells protect the intestine by secreting mucins. In addition to Apc mutations, many CRC patients have Kras gene mutations. Therefore, the researchers also crossed the AMC mouse model with a mutated Kras mouse model. Finally, the researchers examined two human CRC cell lines in vitro. They performed a knockdown of Muc4 and conducted a cellular fractionation study of the cell lines.

“Knockdown (KD) of MUC4 increased the expression of β-catenin, cyclin-D1, and CD44 at the transcript level in LS-180 and HCT-8 cells (Supplementary Figure 3C).”

The Results

The researchers found that Muc4 deletion in the AMC mice resulted in more colorectal tumors with high-grade dysplasia compared to AC and normal mice. Immunohistochemistry staining revealed that AMC and AC mice did not produce any visible goblet cells.

“We observed that in both AMC and AC mice, there was a complete absence or loss of staining in the goblet cells of colon adenoma (Figure 2E), suggesting that disruption of goblet cell function alters the mucin production.”

Muc4 knock-out in AMC mice was associated with an upregulation of Muc13 and a significant loss of Muc2 and Fam3D in CRC tissues. The researchers observed that Muc4 deletion resulted in defective mucus barrier function, reduced intestinal homeostasis and up-regulated β-catenin signaling. In the Kras/AMC mice, they found that the addition of the Kras mutation further aggravated tumors and reduced survival.

Conclusion

The research team found that, in the AMC GEM model (lacking mucin expression), there was an increase in inflammation, DNA damage, tumor burden, and CRC cell proliferation. The study’s findings provide evidence that Muc4 expression is essential for the proper maintenance of the mucus layer and intestinal homeostasis. Furthermore, this research suggests that reduced expression of Muc4 may be associated with aging and a predisposition to colorectal cancer.

“In conclusion, our study suggests that Muc4 has a protective role in CRC progression in an Apc mutant GEM mice model. Muc4 maintains the intestinal homeostasis by upregulation of Muc2 and Fam3D (guardians of the gut) and downregulation of cancer-promoting mucin (Muc13). Additionally, presence of Muc4 prevents the invasion of microbiota and reduction of proinflammatory cytokines and decrease in epithelial cell proliferation by inhibiting β-catenin, c-Myc and CD44 expression. Additional studies are needed to understand the role of Muc4 in conditional KO mouse models and various sub-types of CRC.”

Click here to read the full priority research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Trending With Impact: Do Biomarkers of “Long COVID” Exist?

In a recently published Aging-US paper, researchers investigated potential biomarkers of severe COVID-19 among recovered patients.

Long COVID word cloud

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Among people who have been fortunate to recover from COVID-19, at least 40% had or have long-term lingering effects from this disease. Frequently appearing months after recovery, these “long covid” effects can include (not limited to) fatigue, trouble sleeping, difficulty concentrating, joint or muscle pain, and respiratory issues, such as shortness of breath and chest pain. Researchers are still unsure as to whether or not lasting COVID-19 effects in the lungs are associated with the severity of disease at the time of infection.

“Thus, prospective studies related to outcomes following recovery from COVID-19 might improve our understanding of this disease, its sequelae, and possible interventions to improve this situation.”

Researchers—from Hospital Universitario San PedroCentro de Investigación Biomédica de La RiojaUniversidad de CórdobaHospital Universitario Reina SofíaHospital Costal de SolHCU Lozano BlesaHospital Universitario Marqués de ValdecillaUnidad de Enfermedades InfecciosasHospital Universitario de BurgosVitro LaboratoryInstituto de Investigación-IdiPaz, and Universidad Rey Juan Carlos—conducted a new study aimed at identifying biomarkers of severe disease in patients after hospitalization for COVID-19. Their research paper was published by Aging (Aging-US) on February 16, 2022, and entitled, “Elevated levels of serum CDCP1 in individuals recovering from severe COVID-19 disease.”

The Study

A total of 108 recovered COVID-19 patients admitted to hospitals throughout Spain (46.2% of whom had severe cases) were enrolled in this study. Lung function was measured by the capacity to diffuse carbon monoxide. Samples of serum and induced sputum (phlegm) were collected from the patients and used to evaluate the relationships between patients with residual inflammation in the lungs. Within these samples, the researchers analyzed and compared the levels of 92 protein biomarkers, including various chemokines, cytokines, growth factors, interleukins, and the CUB domain-containing protein 1 (CDCP1)—a cell surface glycoprotein. High levels of CDCP1 were previously observed in some severe cases of COVID-19 in children.

“In COVID-19-infected children who developed acute vasculitis, CDCP1 was one of the most significantly upregulated genes [25], but this complication was not observed in our study.”

The Results

Of all 92 biomarkers, multivariate analysis showed only elevated levels of serum CDCP1 in individuals recovering from severe COVID-19. To their surprise, they also found a positive relationship between CDCP1 and TGFb1 in sputum samples (irrespective of severity). The researchers found a significant difference in lung function (as measured by diffusing capacity for carbon monoxide (DLCO)) between those who had severe cases of COVID-19 and those who had mild/moderate cases. Differences in serum proinflammatory cytokines were not observed between the two groups of recovered COVID-19 patients, indicating that these biomarkers subside after recovery. Correlations between serum and induced sputum levels were detected for only a few biomarkers.

“Independent predictors of severe disease were DLCO <80% and the serum CDCP1 value.”

Conclusion

The authors were forthcoming about the limitations of their study. The team did not use a control group, although, the goal of this study was to investigate the severity of COVID-19. The cohort was relatively small, and the researchers note the need to further study the role of CDCP1. They also suggest that prospective studies should follow patients in recovery from COVID-19 in order to continue improving our understanding of this still novel virus. Such information could aid in the development of interventions to improve patient prognoses long-term.

“In conclusion, although the long-term impact of high serum levels of CDCP1 is still unknown, we should be alert to the potential implications for lung disease. For this reason, it is necessary to follow such patients for longer periods of time to detect and adequately treat potential pulmonary sequelae.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

Trending With Impact: Cognitive Decline Predicted from Middle-Age

Researchers investigated epigenetic and brain aging markers in middle-age for their potential to predict cognitive decline.

Trending With Impact: Cognitive Decline Predicted from Middle-Age

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Aging seems nearly synonymous with brewing cognitive decline, but does it have to be? There are interventions that may help preserve cognitive function with age, however, the first order of business is identifying early biological aging markers that present before symptoms begin emerging. Mid-life biomarkers that can indicate accelerated aging and predict age-related cognitive decline (including Alzheimer’s disease and dementia) may provide humans with enough time to course-correct and improve our quality of life in old age.

The latest to endeavor in search of these early aging markers are researchers from Northwestern University Feinberg School of MedicineUniversity of Texas Health Science Center at San AntonioUniversity of PennsylvaniaBoston University School of MedicineNational Institute on Aging from the National Institutes of HealthUniversity of MinnesotaColumbia University Mailman School of Public HealthKaiser Permanente Division of ResearchUniversity of Texas at AustinUniversity of California San Francisco, and the San Francisco Veterans Affairs Medical Center. Their new research study was published in Aging (Aging-US) as the cover paper in Volume 14, Issue 4, on February 27, 2022. The paper is entitled, “Mid-life epigenetic age, neuroimaging brain age, and cognitive function: coronary artery risk development in young adults (CARDIA) study.”

The Study

In this study, the researchers looked at the associations between cognitive function, epigenetic age and age acceleration measures (using DNA methylation), and brain imaging data in a biracial cohort involving 1,676 healthy human participants. These participants were derived from the Coronary Artery Risk Development in Young Adults (CARDIA) study. The CARDIA study began in 1985 with the aim of tracking changes in cardiovascular disease risk factors among thousands of young-adult to middle-age participants. The average age of participants in this current study was 40 years old.

Participants were evaluated for cognitive function using three tests: the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test B-A (TMTB-A) and the Digit Symbol Coding Test (DSCT). The researchers assessed and re-analyzed the cohort twice (up to 15 years apart). Data were generated for two separate sub-studies. The first sub-study looked specifically at DNA methylation (DNAm) data using GrimAge, PhenoAge, Hannum’s DNAm Age, and Horvath’s DNAm Age. The second sub-study collected neuroimaging data from participants using magnetic resonance imaging (MRI) scans.

“While blood-derived epigenetic aging markers have shown predictive value years before age-related diseases occur [2123], biological aging rates can differ across organ systems, so predictors derived directly from the brain may hold unique information for cognition [2425].”

The researchers note that aging-related brain atrophy occurs in a predictable manner across the human lifespan. Therefore, brain atrophy is the measure of brain aging identified by MRI scans in this study. To translate the atrophy of brain structures into a biomarker of aging, the team leveraged machine-learning algorithms to generate a composite age-related morphological index called the Spatial Pattern of Atrophy for Recognition (SPARE) of Brain Age (SPARE-BA).

“The goal of the present study was to quantify the associations of epigenetic age acceleration and SPARE-BA acceleration with subsequent cognitive performance in a biracial cohort (~40% Black participants and ~60% White participants) of middle-aged adults with 5 to 15 years of follow up.”

The Results

Out of the four epigenetic aging markers examined, the researchers found that GrimAA was uniquely capable of closely predicting worse cognitive outcomes in this middle-aged CARDIA population. In the long term, biomarkers of epigenetic aging were more stable predictors of cognitive decline than the brain aging biomarker. However, changes in SPARE-BA and the SPARE-BA acceleration (SPARE-BAA) index showed stronger associations with cognition over time than any of the epigenetic aging markers. The researchers believe this is because the brain age/aging biomarkers may be more temporally dynamic in association with cognitive decline. When the researchers compared each biomarker’s association with cognition, they found that a combined model of GrimAA and SPARE-BAA demonstrated an improved ability to predict lower cognitive performance.

“GrimAA and SPARE-BAA were not correlated with one another, indicating that they capture distinct facets of biological aging.”

Conclusion

The researchers were forthcoming about limitations in this study. The epigenetic and brain imaging markers were mostly derived from different participants within the study, therefore, other unmeasured factors may have contributed to the study results. Baseline cognitive data was not recorded at younger ages and epigenetic markers were collected at different time points than cognitive and neuroimaging outcomes. These differences inhibited cross-sectional analysis of epigenetic and brain aging. In addition, predictions may be better validated with extended follow-up periods. Nonetheless, this research may have identified two profoundly useful indicators of cognitive decline that could be put to use as early as middle-age—a potential “tipping point” in the human lifespan; when interventions may still prevent irreversible cognitive impairment.

“With further validation, epigenetic and brain aging markers may help aid timely identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal functioning across the lifespan.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Behavioral Aging Study and Ethical Lifespan Assessment of Hybrid Mice

Researchers analyzed the behavior of hybrid mice and presented a novel method to qualitatively estimate natural lifespan.

Lifespan stopwatch
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Mice are frequently used as research models in aging studies. In 2019, researchers from the University of GothenburgR&D AstraZenecaHarvard Medical School, and Karolinska Institutet identified logistical and ethical issues with the standard system of handling murine models in aging studies. Historically, researchers have favored using male mouse models instead of females, especially in pharmaceutical drug discovery and testing. However, half of the human population is female, and thus, females are half of the recipients of pharmaceuticals on the market. There is a need to fill this gap in research by emphasizing the assessment of both male and female subjects in research studies. The second logistical problem is the use of inbred mice. Inbred laboratory mice tend to have strain-specific behaviors that can skew study results. Therefore, there is a need to replace inbred mice with hybrid mice, especially in behavioral aging studies.

Lastly, the researchers addressed lifespan assessment in mice. Due to ethical concerns, many institutions do not allow researchers to study lifespan in mice. These concerns arose from researchers allowing mice to pass away naturally, even if some mice are terminally ill and suffering. In a research paper published by Aging (Aging-US) in 2019, the researchers came up with a novel method of ethically assessing lifespan. They also employed male and female F2 hybrid mice in a behavioral aging study. Their paper was entitled, “Conclusions from a behavioral aging study on male and female F2 hybrid mice on age-related behavior, buoyancy in water-based tests, and an ethical method to assess lifespan.”

Behavioral Aging Studies in Mice

“In this study, F2 hybrid female and male mice were assessed for behavioral tests with the aim to investigate sex differences and age-related alterations.”

The team used various behavioral tests in order to gain a better understanding of the behavioral effects of aging in female and male F2 hybrid mice. Behavioral tests included an open-field test in an activity box, the shuttle box passive avoidance test, physiological analyses for behavioral phenotyping at seven, 15 and 22 months of age, and a swim test to measure immobility. Immobility in the swim test was an indicator of depressive-like behavior.

In sum, the researchers demonstrated that decreased exploratory behavior is a robust behavioral marker of aging in both male and female hybrid mice. However, altered learning, memory and depressive-like behavior were not significant markers of aging in these models. To this end, the team did not find sex differences in learning or memory using the passive avoidance test. In females, fat mass accounted for 30-46% of the observed increase in depressive-like behavior compared to males.

“This novel finding emphasizes the need to control for body composition in water-based tests.”

Ethical Murine Lifespan Assessment

The ethical method of lifespan assessment the researchers devised involves using estimates of lifespan. In a separate cohort from the behavioral studies, the researchers created this lifespan estimation by separating mice with signs of pain or severe disease from the healthy aging mice. The ill animals were euthanized and then included in two separate data curves. In one curve, the euthanized animals were counted as if their time of death was from natural causes (an underestimation of their lifespan). The researchers then made a second data curve in which they calculated that the euthanized animals as if they had been as healthy as their littermates (an overestimation of their lifespan since the euthanized animals were terminally ill). These curves created an interval that was used as the minimum and maximum lifespan of this cohort. 

“We think this is a really good method that we hope people will start using in lifespan analysis,” said Malin Hernebring, from the University of Gothenburg and R&D AstraZeneca, in a recent Behind the Study interview with Aging-US

Conclusion

The researchers presented a novel method to estimate natural lifespan in survival studies, in which animals in pain or with severe disease are not left to suffer until the end of their natural lifespan. This new method provides a qualitative estimation of natural lifespan, without the expense of animal welfare. The study also showed that F2 hybrid mice are effective in behavioral aging studies, and that fat mass partially accounts for increased immobility in aging female mice. 

The researchers hope that their findings will lead to changes in the way aging research is conducted. In particular, they hope that more emphasis will be placed on testing both male and female subjects, that inbred mice will be replaced with hybrid mice and that their ethical method of lifespan assessment in mouse models is adopted at scale.

“In summary, this work is the first behavioral phenotypic aging study to use hybrid mice and include analyses of both sexes.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

Trending With Impact: Can Job Stress Cause Epigenetic Aging?

The association between job-related stress and epigenetic aging was investigated using five epigenetic clocks and a Finnish cohort.

Job stress

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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In aging research, recent evidence has encouraged more focus on investigating socioeconomic status (SES) and its role in human health trajectories. Previous studies have used DNA methylation measures and epigenetic clocks to demonstrate a consistent association between low SES and epigenetic age acceleration (EAA). Moreover, researchers have identified a need to further investigate the relationship between SES characteristics and aging.  

“Little is known whether current occupational characteristics or job-related stress – crucial SES characteristics – are associated with EAA.”

Recently, researchers—from Imperial College LondonUniversity of SassariUniversity of Eastern FinlandKarolinska InstitutetUniversity of Oulu, and the Italian Institute for Genomic Medicine—conducted a research study in an effort to help elucidate potential mechanisms by which work characteristics and job stressors may be impacting health and accelerating aging. Their trending research paper was published by Aging (Aging-US) on February 2, 2022, and entitled, “Work-related stress and well-being in association with epigenetic age acceleration: A Northern Finland Birth Cohort 1966 Study.” 

The Study

The researchers in this study included 604 participants from the Northern Finland Birth Cohort 1966. Participants in this cohort were all born in the provinces of Oulu and Lapland, Finland, in 1966. DNA samples were collected and used to determine the relationship between biomarkers of aging, job stress and common environmental factors associated with age acceleration, including obesity, smoking, alcoholism, education status, and physical activity. The team used five different epigenetic clocks as biomarkers of aging: HorvathAA, HannumAA, PhenoAgeAA, GrimAgeAA, and DunedinPoAm.

“In this work, we assessed the association (and its magnitude) of five biomarkers of epigenetic age acceleration with work-related stress and well-being indicators (as well as other employment characteristics) in the Northern Finland Birth Cohort 1966, at 46 years old.”

Participants also filled out a clinical examination questionnaire, a modified Karasek’s Job Content Questionnaire (to assess job strain) and the Occupational Stress Questionnaire (to measure effort-reward imbalance). A number of descriptive statistics were collected from each participant, including body mass index (BMI); educational level; alcohol consumption; smoking habits; physical/leisure activity; job status (employed/unemployed); employer type (private or state/municipality); occupational group (white-collar or blue-collar); and job exposure. The researchers defined “job exposure” as job strain, effort-reward imbalance, overcommitment, occupational physical activity, work-favoring attitude, job security and work engagement, history, hours, and shift. 

The Results

After using linear regression models to analyze the adjusted and unadjusted pooled data (males and females together), the researchers found that job strain was not significantly associated with EAA using any of the epigenetic clocks. All five clocks associated smoking and obesity with accelerated aging (at varying significance). However, alcohol use (even heavy use) was not significantly associated with accelerated aging on any of the clocks. PhenoAgeAA associated job strain, active work and white-collar work (compared to blue-collar) with decreased aging. According to the Hannum and HorvathAA biomarkers of aging, people who worked more than 40 hours per week showed increased EAA.

“Once we stratified analyses by sex, a different pattern of association emerged, with women leading on the statistically significant results.”

Next, the researchers further stratified the results by sex. In men, high-intensity physical effort at work had a decreased aging effect. However, for women, high-intensity physical effort at work had an increased aging effect. The researchers point out that these clocks may have contradictory result due to the fact that women and men often present with diverse, sex-specific epigenetic patterns. While a direct correlation between job stress and epigenetic aging have yet to be proven, the degree of association between work characteristics and biomarkers of epigenetic aging in this study did vary by sex.

Conclusion

“This paper is one of the first attempts to address the working dimension of epigenetic age acceleration indicators, to the best of our knowledge.”

The Northern Finland Birth Cohort 1966 is a useful sample for studying a general population, and many confounders were removed in doing so. However, the researchers were forthcoming about some limitations that remained in this study. The unique characteristics of the cohort, as well as the questionnaires, may be responsible for the results seen in the study. The researchers suggest that additional studies be carried out in other societies and on different types of jobs to account for gender differences. 

“Our results suggest that women and men present different associations with different epigenetic distributions regarding work-related stress indicators.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

Trending With Impact: Radiation, Senescence and Senotherapeutics

Researchers examined the effects of thoracic radiation-induced senescent cells on tumor progression, and the role of senotherapeutics to mitigate these effects.

Radiation therapy, advanced medical linear accelerator in therapeutic oncology to treat cancer
Radiation therapy, advanced medical linear accelerator in therapeutic oncology to treat cancer

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Radiation therapy is a highly-efficacious inducer of cancer cell death. With this being said, radiation has also previously been shown to cause premature senescence in the lung parenchyma. Senescence in cancer cells was previously only thought of as a mechanism capable of suppressing tumor cell proliferation by halting the cell cycle. However, a growing body of evidence shows that senescent cells may play a pro-tumorigenic role in cancer.

In the tumor microenvironment, the accumulation of senescent cells can become tumorigenic due to a lack of normal tissue stem cells and due to the expression of the senescence-associated secretory phenotype (SASP). SASP expression is when senescent cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases. In addition to reinforcing senescence, SASP can create a biological environment that is immuno-suppressed and tumor-permissive. Radiation-induced senescence has previously been shown to have negative impacts on cancer patients.

“Cells that have undergone premature senescence due to stress, such as irradiation, are resistant to apoptotic cell death and effectively escape immune surveillance, resulting in their accumulation in tissue over time.”

Recently, researchers from the National Cancer Institute investigated the irradiated lung and the impact of radiation-induced senescent parenchymal cells on tumor growth. They also explored three senotherapeutics, rapamycin, INK-128 and ABT-737, for their potential to mitigate radiation-induced senescence. On February 12, 2022, the team’s priority research paper was published on the cover of Aging (Aging-US) Volume 14, Issue 3, and entitled, “Senescence-associated tumor growth is promoted by 12-Lipoxygenase.”

The Study

In this study, researchers intravenously injected melanoma cells into murine models two, four and eight weeks after daily fractions of thoracic irradiation exposure. There was also a control arm of unirradiated murine models. Tumor development was monitored by the number and size of the nodules in lung tissues. The number of cells exhibiting senescent activity was also recorded after two, four and eight weeks of thoracic irradiation. Their data demonstrated a correlation between the time points when tumors developed in the irradiated lungs and a marked accumulation of senescent cells.

“As previously described, in irradiated lungs, senescent cells increased significantly 4 and 8 weeks after IR compared to age matched unirradiated controls (Figure 1A).”

A characteristic of oncogene- and stress-induced senescence is the activation of mTOR signaling. Given this connection, the researchers conducted parallel studies evaluating senostatic agents capable of targeting the mTOR pathway, rapamycin and INK-128, and a senolytic agent to selectively eliminate senescent cells, ABT-737.  The data showed that rapamycin and INK-128 significantly reduced the number of tumor nodules in the lungs of irradiated mice compared to the controls. ABT-737 demonstrated reduced pulmonary senescence in irradiated mice.

The researchers also studied 12-Lipoxygensae (12-LOX), an enzyme that metabolizes a certain SASP molecule previously implicated in pulmonary senescence: 12(S)-HETE. 12-LOX is a known contributor to radiation-induced senescence and lung injury. The team specifically focused on the role of 12-LOX in pulmonary senescence and its impact on radiation-enhanced tumor growth. They found that inhibiting 12-LOX activity reduced radiation-induced lung senescence and mitigated radiation-enhanced tumor growth.

“Finally, we link senescence associated 12-LOX activity and production of 12(S)-HETE to the observed enhanced tumor growth after irradiation.”

Conclusion

In sum, the researchers found that radiation therapy can induce senescence in the lung parenchyma and also enhance tumor growth. The contribution of senescence in tumor progression was emphasized by the protection delivered by the mTOR-targeted senostatic and senolytic agents. This important discovery could lead to new therapies for cancer patients who are undergoing radiation therapy.

“Together, this study demonstrates the critical role of senescence in mediating radiation-enhanced tumor growth and identifies Alox12 as an important player in this phenomenon. Treatment with a senostatic agent, INK-128, identified in this study, or with agents like rapamycin and ABT-737 suggested their potential therapeutic use in alleviating radiation associated tumor growth.”

Click here to read the full priority research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

Trending With Impact: ARDD21 Meeting Report Highlights

Read a brief summary of a meeting report from the 8th Annual Aging Research and Drug Discovery (ARDD21) meeting. 

ARDD21

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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The 8th Annual Aging Research and Drug Discovery (ARDD21) meeting was held in Copenhagen, Denmark, from August 30 to September 3, 2021. This meeting was attended by over 130 people on-site, with an additional 1800 people engaged online. The focus of this meeting was the current landscape of aging research and various ways it can be applied to drug discovery. Topics included: age-dependent control of cellular maintenance processes, longevity pathways, artificial intelligence-based drug screening, cellular stress and aging, the benefits of dietary restriction, stem cell rejuvenation, senolytics as an aging therapeutic, diverse models of aging, aging clocks and biomarkers of aging, new ideas in preclinical and clinical aging research, the longevity industry landscape, and a Longevity Medicine Workshop.

In total, there were 75 presentations given at ARDD21 by prominent and dedicated aging researchers. The meeting was thoroughly summarized in a paper published in Aging (Aging-US) Volume 14, Issue 2, entitled, “Meeting Report: Aging Research and Drug Discovery.”

ARDD21 Meeting Report Highlights

One of the keynote presentations was given by Nir Barzilai from the Albert Einstein College of Medicine. He discussed his work on aging and how it can be applied to drug discovery. One interesting finding that he discussed was that many drugs currently used to treat chronic diseases, such as diabetes and heart disease, also have the potential to treat aging. This is due to the fact that many diseases are symptoms of aging, and thus, treating the underlying cause (aging) can in turn treat the symptoms.

Another keynote presentation was given by James Kirkland from the Mayo Clinic. He discussed his work on developing therapies to target senescent cells. Senescent cells can accumulate with age, and their presence has been linked with a variety of age-related conditions such as arthritis, cancer and heart disease. Kirkland’s team has developed a number of potential therapies to eliminate or reduce the number of senescent cells in the body, and he is currently testing them in clinical trials.

Professor Dame Linda Partridge from Max Planck Institute for Biology of Ageing presented on aging and the importance of intestinal homeostasis. Her studies involved rapamycin treatment to act on the longevity pathway mTOR, which revealed that short term and early treatment with rapamycin extends lifespan in D. melanogaster as much as chronic rapamycin treatment. Yu-Xuan Lu, another researcher from the Max Planck Institute for Biology of Ageing, demonstrated the existence of an unconventional intestine sex-specific TORC1-histone axis which uncovers a new aspect of improved longevity with rapamycin.

Brian Kennedy from the Buck Institute for Research on AgingNational University of Singapore and National University Health System showed how Alzheimer’s disease can be used as a model of neuronal aging. Presenting their new WormBot, Matt Kaeberlein from the University of Washington described a “set it and forget it” method of large-scale intervention testing in roundworms (C. elegans). 

“He stressed the importance of broad and unbiased screening of intervention beyond known pathways and in different combinations [56].”

Aging (Aging-US) Editorial Board member Alexey Moskalev from the Russian Academy of Sciences presented on the disruption of hydrogen sulfide homeostasis and its association with aging, and therefore, its potential as a gero-therapeutic target. David Sinclair from Harvard Medical School (also on the Aging Editorial Board) discussed aging-driven epigenetic and gene expression changes in the central nervous system. He showed that this can be safely reversed to restore vision by inducible adeno-associated viruses expressing polycistronic Oct4, Sox2 and Kif4, and that the effect is dependent on DNA demethylation. Finally, a Longevity Medicine Workshop was held with a panel of experts aimed to inspire young students to engage in longevity research. This panel included Aging Editorial Board members Alex Zhavoronkov, Alexey Moskalev and Mikhail Blagosklonny (Editor-In-Chief).

Conclusion

Overall, the ARDD21 meeting was a fruitful exhibition of experts from all areas of aging research that came together to share their latest findings in the field. The highlights in this blog pale in comparison to the thoughtful details included in the original meeting report. 

Click here to read the full meeting report published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

Trending With Impact: Therapeutic Strategy Improves Cell Senescence

In the cover paper of Aging (Aging-US) Volume 14, Issue 2, researchers discovered a potential therapeutic strategy to target senescent cells and combat aging and age-related diseases.

The Trending With Impact series highlights Aging (Aging-US) publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Cellular senescence appears to be a phenomenon fundamentally ingrained within the aging process and linked to age-related diseases. Characterized broadly by permanent cessation of the cell cycle, cellular senescence may not be as permanent as once thought. 

Researchers from Incheon National University and Korea University conducted a new study exploring analogs of oxazoloquinoline and their potential to alleviate cellular senescence. Their trending research paper was published as the cover of Aging (Aging-US) Volume 14, Issue 2, and entitled, “Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence.”

THE STUDY

Adenosine triphosphate (ATP) is an energy-carrying molecule found in all living cells. In order to meet the energy demands of the cell, the primary function of the mitochondria is to produce ATP. The maintenance of mitochondrial metabolism is inseparably linked with the regulation of senescence. Therefore, dysfunctional mitochondria has been considered as both a target and the cause of senescence. In addition to a marked decrease in ATP production, senescent cells also increase the expression of inflammatory cytokines, including interleukin 33, or IL-33. The researchers believe that reducing IL-33 may be a possible intervention to reduce senescence in aging patients and age-related diseases.

“In this study, using in-house compound library containing 20 oxazoloquinoline analogs designed to IL-33 inhibitors [9], we aimed to identify compounds capable of ameliorating senescence.”

The researchers investigated 20 oxazoloquinoline analogs using in vitro assays of senescent human diploid fibroblasts and embryonic kidney cells. Efficacy of the candidate compounds was determined using a screening strategy to measure their capacity to increase cell number. Cell numbers were measured between zero and 20 days after compound exposure. The researchers also measured indicators including mitochondrial membrane potential, reactive oxygen species (ROS) levels and p21 expression. They found that the analog KB1541 led to the maximum cell number increase, the recovery of mitochondrial function and the alleviation of cellular senescence. The researchers suggest that KB1541 could be a promising therapeutic agent for use in aging-related diseases.

“The increase in mitochondrial cristae length by KB1541 could be explained by previous findings showing that the increase in ATP generation exerted beneficial effects in mitochondrial function including increases in calcium buffering capacity and decrease in overall ROS production [48].”

CONCLUSIONS

“Taken together, our study provides evidence that the fine-tuning of ATP synthase 5 alpha/beta dimerization by KB1541 can induce mitochondrial functional recovery, concomitant recovery of senescent phenotypes, rendering the use of KB1541 as a potentially advantageous therapeutic strategy in aging and age-related diseases.”

The authors acknowledged that further studies are needed to clarify the exact relationship between IL-33 and mitochondrial energy metabolism. Further studies are also needed to investigate whether other IL-33 inhibitors can modulate senescence by the mechanisms found in the study. This research provides valuable insight into the potential of oxazoloquinoline analogs as novel therapeutic agents for aging and age-related diseases. With further exploration, their findings could lead to new therapeutic strategies to combat aging.

“The role of IL-33 in senescence is not clearly elucidated, therefore discovery of a novel interacting partner will provide clues toward revealing its function.”

Click here to read the full research paper published by Aging (Aging-US).

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

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