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

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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 Medicine, University of Chicago, George Mason University, University 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).

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

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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.

For media inquiries, please contact [email protected].

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Trending With Impact: Intestinal Balance, Colorectal Cancer and Muc4

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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 Center, Baylor College of Medicine, University 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).

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

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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 [email protected].

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Trending With Impact: Cognitive Decline Predicted from Middle-Age

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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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Listen to an audio version of this article

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 Medicine, University of Texas Health Science Center at San Antonio, University of Pennsylvania, Boston University School of Medicine, National Institute on Aging from the National Institutes of Health, University of Minnesota, Columbia University Mailman School of Public Health, Kaiser Permanente Division of Research, University of Texas at Austin, University 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 [21–23], biological aging rates can differ across organ systems, so predictors derived directly from the brain may hold unique information for cognition [24, 25].”

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).

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

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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 [email protected].

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Aging and Circadian Rhythm: Does a Conserved Link Exist?

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In the Aging (Aging-US) Volume 13, Issue 24, cover paper, researchers conducted a study suggesting that the circadian rhythm is subjected to aging-related gene alterations.

Figure 6. Matching of our CR-related DEGs evidenced to be regulated with aging with a curated human CR network.
Figure 6. Matching of our CR-related DEGs evidenced to be regulated with aging with a curated human CR network.
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Chronobiology is the study of biological rhythms. The human circadian system is a biological process known to regulate the sleeping and waking cycle (circadian rhythm; CR). Components of the circadian system are known as ​​clock genes. Clock genes generate daily oscillations of gene expression and interact as an intricate network to influence biological processes in organisms, tissues and cells. This system is primarily regulated by Earth’s day and night cycles (light and darkness), though it can be affected by other factors, including nutrition, cellular devices, stress, illness, jet lag, and aging.

“It is well established that aging interferes with the regulation of the circadian system, which, in return, contributes to the manifestation and progression of aging-related diseases (reviewed in [4, 5]).”

Across an organism’s lifespan, changes in circadian rhythm take place. These changes can cause aging-related diseases to become more prevalent. Studies have also shown that age-independent alterations to the circadian system can result in premature aging. This interrelation between aging and CR means that aging may play a role in the circadian system and that the circadian system may play a role in aging. However, researchers have not yet fully illuminated the impact of aging-related circadian system changes on healthy organs and tissues. 

“Whether aging-related changes of the circadian system’s regulation follow a conserved pattern across different species and tissues, hence representing a common driving force of aging, is unclear.”

The Study

In an effort to identify circadian rhythm regulatory patterns over the course of aging, researchers—from Friedrich Schiller University Jena, FLI Leibniz Institute for Age Research, Jena University Hospital, German Center for Integrative Biodiversity Research, and European Virus Bioinformatics Center—performed inter-species and inter-organ transcriptional analyses. The research paper was published in December of 2021 as the cover of Aging (Aging-US) Volume 12, Issue 24, and entitled, “Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging.”

“Here, we used RNA-Seq data to profile the regulation of CR-related genes of 4 different species in a cross-sectional study in individuals ranging from young mature to old-age categories.”

In this cross-sectional study, the researchers used data from 329 RNA sequencing libraries to identify differentially expressed genes in transcriptional profiles among humans, house mice, zebrafish, and the extremely short-lived turquoise killifish. All human donors were classified into the following age groups of 14 to 15 individuals: mature (24–29 years), aged (60–65 years), and old-age (75–79 years). The other species were categorized into their respective age groups. Organs, including the brain, blood, liver, and skin, were examined and then compared between the four species.

The researchers found that two circadian rhythm-related genes (dec2 and per2) were altered in all four species, primarily in early- and late-aging groups. Four genes (cirp, klf10, nfil3, and dbp) with aging-related expression patterns were found in several organs and species. In total, the researchers identified six genes (in several tissues from at least three out of the four species) that function at all regulation levels of circadian rhythm with apparently conserved age-associated regulation.

Conclusion

“​​Thus, these genes might represent a conserved link between the circadian system and aging.”

This study confirms work from previous studies and extends them by providing a new dataset linking circadian rhythm factors to physiological aging across four evolutionarily distinct species. Whether circadian rhythm regulation is the cause or a consequence of the aging process still remains to be explored. The researchers note that their non-synchronized cross-sectional approach should be replicated in the future and include an additional dataset based on a longitudinal study design, tissue synchronizations across species of interest and to potentially analyze anatomic sub-regions of the brain.

“In summary, our results show that modulations in CR-related gene transcription throughout aging are a conserved trait that is traceable across evolutionarily diverse species, ranging from humans to mice and fish.”

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

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

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research and other topics. 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 [email protected].

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