How Menopause Changes Brain Structure and Connectivity

In this study, researchers use neuroimaging to see how menopause alters brain structure and connectivity in postmenopausal women.

Menopause marks the beginning of the next biological chapter in a woman’s life. Characterized by the natural ebb of reproductive hormones (particularly estrogen), menopause ushers in a new season of aging. This hormonal shift not only signifies a transition in fertility but also influences systemic health. The menopause-associated decline in estrogen has been associated with various health issues, including alterations in brain structure and function. However, the mechanics of this phenomenon are still poorly understood. A greater understanding of how menopause alters the brain could aid in the early detection, and possible prevention, of neurodegenerative disease.

In a new study, researchers Gwang-Won Kim, Kwangsung Park, Yun-Hyeon Kim, and Gwang-Woo Jeong from Chonnam National University used neuroimaging to shed light on how menopause alters brain morphology and functional connectivity in postmenopausal women. On March 23, 2024, their research paper was published as the cover of Aging’s Volume 16, Issue 6, entitled, “Altered brain morphology and functional connectivity in postmenopausal women: automatic segmentation of whole-brain and thalamic subnuclei and resting-state fMRI.” 

“To the best of our knowledge, no comparative neuroimaging study on alterations in the brain volume and functional connectivity, especially focusing on the thalamic subnuclei in premenopausal vs. postmenopausal women has been reported.”

The Study

The decline in estrogen levels during menopause has been linked to an elevated risk of neurodegenerative diseases, notably Alzheimer’s disease (AD). Estrogen plays a pivotal role in modulating neurotransmitter systems, neurotrophins, and brain cytoarchitecture, and there is evidence that these interactions also affect mood, memory, and cognition. The biological mechanisms underlying the increased AD risk in postmenopausal women are not fully understood.

In this study, 21 premenopausal women and 21 postmenopausal women were subjected to magnetic resonance imaging (MRI). The researchers utilized T1-weighted MRI and resting-state functional MRI data to assess differences in brain volume and seed-based functional connectivity. For statistical analysis, they employed multivariate analysis of variance, factoring in age and whole brain volume as covariates, to compare the surface areas and subcortical volumes between the two groups.

Results

Postmenopausal women showed significantly smaller cortical surface, especially in the left medial orbitofrontal cortex (mOFC), right superior temporal cortex (STC), and right lateral orbitofrontal cortex, compared to premenopausal women. These findings suggest that diminished brain volume may be linked to menopause-related symptoms caused by lower sex hormone levels.

In addition to structural changes, the functional connectivity between the brain regions also showed changes. The study found significantly decreased functional connectivity between the left mOFC and the right thalamus in postmenopausal women — reinforcing the hypothesis that the left orbitofrontal-bilateral thalamus connectivity is associated with cognitive impairment. Although postmenopausal women did not show volume atrophy in the right thalamus, the volume of the right pulvinar anterior (PuA), a significant thalamic subnuclei, was significantly decreased. Decreased PuA volume in postmenopausal women is closely related to decreases in female sex hormone levels following menopause.

Expectedly, the study found a significant difference in age and sex hormone levels between premenopausal and postmenopausal women. Postmenopausal women had lower total estrogen and estradiol (E2) levels and higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels than premenopausal women. Estrogen levels were positively correlated with the surface area of the left mOFC, right STC, and right lOFC, as well as the volume of the right PuA.

“Concerning the close connection between the estrogen level and STC volume, our findings support a potential role of decreases in sex hormones following menopause due to the correspondent brain structural atrophy. However, further study is needed to elucidate the specific cognitive and emotional implications in connection with these structural changes.”

Conclusions & Future Directions

Postmenopausal women showed significantly lower left mOFC, right lOFC, and right STC surface areas, reduced right PuA volume, and decreased left mOFC-right thalamus functional connectivity compared to premenopausal women. These findings provide novel insight into the structural and functional changes in the brain associated with menopause. However, further research is needed to validate these findings in a larger cohort and to understand the potential cognitive implications of these changes.

“Our findings provide novel insight into the structural and functional changes in the brain associated with menopause.”

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

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.

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3 Domains of Well-Being Extend Elderly Mobility and Longevity

In Aging’s Volume 14, Issue 15, cover paper, researchers hypothesized that multidimensional well-being may prolong mobility-limitation-free survival and longevity among older adults.

3 Domains of Well-Being Extend Elderly Mobility and Longevity
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The Trending With Impact series highlights Aging publications (listed as “Aging (Albany NY)” by Medline/PubMed and “Aging-US” by Web of Science) 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.

The word “well-being” is commonly used in workplace environments, therapy sessions, doctor’s offices, books, online, and elsewhere. However, the definition of this word seems to differ across varying contexts, cultures, traditions, values, and even biological sexes. Below are four definitions of well-being:

  • “noun: [Well-being is] the state of being comfortable, healthy, or happy.” — Oxford English Dictionary
  • “In simple terms, well-being can be described as judging life positively and feeling good.” — Centers for Disease Control and Prevention
  • “The meaning of WELL-BEING is the state of being happy, healthy, or prosperous : welfare.” — Merriam-Webster Dictionary
  • “Well-being, or wellbeing, also known as wellness, prudential value or quality of life, refers to what is intrinsically valuable relative to someone. So the well-being of a person is what is ultimately good for this person, what is in the self-interest of this person.” — Wikipedia

Based on these definitions, one could argue the root meaning of well-being may be distilled down to individual happiness and prosperity that contributes to healthy aging. However, this prosperity and happiness is not anchored to only one domain of well-being. There are three domains of being well, which include behavioralsocial and psychological well-being.

Aging & Well-Being

“Successful aging is a multidimensional construct covering behavioral, social, and psychological domains of well-being, all amenable to individual actions and public health interventions [14].”

Successful, or healthy, aging may be the result of adherence to several protective factors simultaneously within all three of the well-being domains. Previously, the majority of research on healthy aging has been limited to a single domain per study. In a new study, researchers Marguerita Saadeh, Xiaonan Hu, Serhiy Dekhtyar, Anna-Karin Welmer, Davide L. Vetrano, Weili Xu, Laura Fratiglioni, and Amaia Calderón-Larrañaga (from Karolinska InstitutetKarolinska University HospitalStockholm UniversityLund University, and Stockholm Gerontology Research Center) believe that the vast heterogeneity in aging phenotypes cannot be explained by one domain of well-being alone. On July 18, 2022, their research paper was published on the cover of Aging’s Volume 14, Issue 15, and entitled, “Profiles of behavioral, social and psychological well-being in old age and their association with mobility-limitation-free survival.”

“Despite the rising evidence supporting a multidimensional construct of successful aging, most longitudinal studies still fail to cover well-being indicators belonging to different domains, as shown by the disproportionate amount of literature focusing exclusively on lifestyle factors [4548].”

Three Domains of Well-Being: 10 Indicators

In their current study, the researchers selected 10 indicators of behavioral, social and psychological well-being: 1) Behavioral: Mediterranean diet, smoking, physical leisure activities, and mental leisure activities; 2) Social: Social leisure activities (i.e., social participation), social connections and social support; 3) Psychological: life satisfaction, negative affect and positive affect.

Blue zones” are areas around the world with high concentrations of centenarians, or people who live to be over 100 years old. A prevalent diet among people living in blue zones is the Mediterranean diet. The Mediterranean diet consists of fruits, vegetables, whole grains, beans, nuts/seeds, lean poultry, fish, seafood, dairy, eggs, and extra virgin olive oil. This diet has been closely studied as a protective factor of healthy aging.

The psychological well-being indicator listed as “negative affect” refers to the degree to which a person feels guilt, anger and fear, and the following features are considered: distressed, upset, scared, nervous, and afraid. “Positive affect” considers the extent to which a person is active, inspired, determined, alert, and enthusiastic. For additional explanations, the remaining indicators of well-being used in this study are expounded in thorough detail within the research paper itself.

Aging & Mobility

“Mobility decline precedes disability and premature death, and is therefore considered an optimal early indicator of physical function decay among older adults [34].”

The simple ability to exercise, complete day-to-day chores and maintain personal hygiene all rely on a minimum range of physical mobility. A sedentary lifestyle is a well-recognized risk factor for chronic diseases, such as obesity, type 2 diabetes, cardiovascular disease, and some forms of cancer. Furthermore, mobility limitations are associated with social isolation, depression and cognitive decline. The researchers in this study aimed to identify well-being profiles and their association with mobility-limitation-free survival.

“The specific aims of this study were: 1) to identify distinct well-being profiles among men and women separately, by using latent class analysis; 2) to determine which of these profiles are associated with the greatest benefit in terms of mobility-limitation-free survival; and 3) to quantify these potential benefits in absolute terms by calculating differences in median age at onset of mobility limitation or death across profiles.”

The Study

The study population consisted of 1488 functionally healthy individuals (after all exclusion criteria were applied to the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) population-based study). In addition to collecting self-reported data on the 10 indicators of behavioral, social and psychological well-being listed above, the researchers included data on the participants’ covariates. Covariates included age, education, number of chronic diseases, mini-Mental State Examination score (MMSE), and NEO Five-Factor Inventory (NEO-FFI) questionnaire. At the beginning of the study (baseline), the average age in the cohort was 69 years old (with a standard deviation of +/- 8.3 years). Ninety-one percent of participants had at least a high-school-level of education. Females (59%) composed the majority of the cohort.

“In this study, we used latent class analysis to detect data-driven subgroups of people with similar well-being profiles according to behavioral (diet, smoking, and physical and mental leisure activities), social (social participation, connections, and support) and psychological (life satisfaction, positive and negative affect) well-being indicators, as defined by the Centers for Disease Control and Prevention (CDC) [25].”

Since men and women tend to behave differently when it comes to multiple factors of well-being, the researchers stratified their analyses by sex. They scheduled regular followed-ups with these participants over the course of 15 years. Well-being profiles were derived from the 10 well-being indicators using latent class analysis. Endpoints were defined as mobility-limitation-free survival, limited mobility or death. Limited mobility was defined as having a walking speed below 0.8 meters per second.

“A composite endpoint, considered to be an indicator of mobility-limitation-free survival, was operationalized by taking into account the time from study entry until the development of mobility limitation (i.e., walking speed <0.8m/s) or death, whichever occurred first.”

Results

At baseline, the researchers identified three well-being profiles among both men and women that followed a clear gradient in all behavioral, social and psychological indicators throughout the study. Participants categorized in the best well-being profile had high adherence to the Mediterranean diet, the lowest proportion of current smokers, high engagement with leisure activities, and the highest levels of social and psychological well-being. Those in the intermediate well-being profile had low/moderate adherence to the Mediterranean diet, a higher proportion of former/never smokers, and moderate levels of social and psychological well-being. (Men in the  intermediate well-being profile had a low/moderate engagement in leisure activities, while women had moderate/high engagement levels.) Participants in the worst well-being profile had low adherence to the Mediterranean diet, a higher proportion of former/never smokers, the lowest levels of leisure activity engagement, and the lowest levels of social and psychological well-being.

To examine the association between these well-being profiles and the incidence of mobility limitation or death, the researchers used Cox and Laplace regression models and applied sensitivity analyses to the data.

“In agreement with the Cox regressions, results from Laplace regressions showed that men in the intermediate and best profiles survived 1 and 3 years longer without mobility limitations, respectively, compared to those in the worst profile after adjustment for potential confounders (Figure 2). Women in the intermediate and best profiles lived 2 and 3 years longer without mobility limitations, respectively, compared to those in the worst profile.”

Conclusion

The well-being profiles of older adults are associated with their risk of developing mobility limitations and death. Those in the best well-being profile had the lowest risk, while those in the worst well-being profile had the highest risk. These findings suggest that interventions to improve multi-domain well-being in older adults may improve longevity and help reduce the incidence of mobility limitations in old age. Although this study has many strengths, the researchers were forthcoming about its limitations. Future studies are recommended to confirm these findings.

“While theoretical insights into different models of successful aging are on the rise, empirical evidence from population-based longitudinal data on the complex interplay among the distinct well-being domains and their association with person-centered outcomes, such as mobility-limitation-free survival, is currently lacking. This study addresses such an important gap and provides further evidence to better understand and promote functional independence in community-dwelling older adults through primary prevention multi-domain interventions.”

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

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Aging 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: Humanin G Treatment in AMD Reduces Inflammation

In the cover paper published in Aging-US Volume 14, Issue 10, researchers investigated a potential therapeutic intervention to reduce chronic inflammation in age-related macular degeneration (AMD).

Trending With Impact: Humanin G Treatment in AMD Reduces Inflammation

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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One of the leading causes of vision loss among aging populations in the United States, and worldwide, is age-related macular degeneration (AMD). The progression of this disease is known to be driven by inflammatory processes. However, the exact inflammation-associated proteins and the mechanisms that drive them have not yet been fully elucidated.

“Inflammation plays a crucial role in the etiology and pathogenesis of AMD (Age-related Macular Degeneration).”

In a new study in Aging (Aging-US), researchers from the University of California Irvine and the University of Southern California investigated a potential therapeutic intervention to reduce chronic inflammation in AMD and delay or prevent retinal degeneration. On May 16, 2022, this trending research paper was published on the cover of Aging’s Volume 14, Issue 10, and entitled, “Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD).”

“Our discovery is novel and may contribute to the development of therapeutics/ tools for reducing inflammation to alleviate AMD disease pathology.”

The Study

Humanin G (HNG) is a naturally produced peptide that may play a pivotal role in tissue homeostasis and normal functioning throughout the body—including the eyes. Previous studies have shown that high-intensity exercise and resistance training positively correlate with protein levels of Humanin G in human plasma and skeletal muscle. Studies have also shown that Humanin G protein levels negatively correlate with aging. In this study, researchers investigated the impact of exogenous Humanin G on markers of inflammation in AMD cells. 

“Moreover, treatment with exogenous Humanin G is known to reduce the expression of markers associated with aging-related disorders [32]. Therefore, we tested the effects of Humanin G on inflammatory markers in this study.”

First, the researchers measured levels of inflammation-associated proteins (including cell adhesion molecules, cytokines and chemokines) among samples of AMD plasma and normal (control) plasma. AMD plasma showed higher protein levels of inflammation markers compared to control plasma samples. Next, the researchers used the ELISA assay to measure Humanin G protein levels in the plasma of both AMD patients and normal subjects. They found that, in AMD patients, protein plasma levels of Humanin G were significantly lower compared to normal subjects. 

“In the current study, we found that the plasma levels of endogenous Humanin protein were significantly lower by 36.58 % in AMD patients compared to that in age-matched normal subjects.”

Exogenous Humanin G was then added to AMD and normal (control) cybrids derived from clinically characterized AMD patients and normal (control) subjects. Cell lysates were extracted from untreated and Humanin G-treated AMD and normal cybrids. Levels of inflammatory proteins were measured using the Luminex XMAP multiplex assay. The researchers observed that protein levels of inflammation markers previously elevated in AMD cells were reduced after Humanin G treatment. 

“To our knowledge, this is the first report that confirms the protective role of Humanin G against inflammation in AMD RPE transmitochondrial cybrid cells and it is significant because reducing ocular inflammation could alleviate its damaging effects observed in the RPE cells that eventually lead to retinal degeneration in AMD pathogenesis.”

Conclusion

“In conclusion, we present novel findings that: A) show reduced Humanin protein levels in AMD plasma vs. normal plasma; B) suggest the role of inflammatory markers in AMD pathogenesis, and C) highlight the positive effects of Humanin G in reducing inflammation in AMD.”

Results in this study are significant because treatment with exogenous Humanin G may be able to revert the abnormal levels of inflammatory proteins that are found in AMD patients back to (or near) normal ranges. These findings may lead to novel therapeutics that can improve AMD disease trajectory. 

“Further studies are required to gain an in-depth understanding of the mechanisms underlying Humanin G-mediated suppression of inflammation in AMD and to establish Humanin G’s therapeutic potential as an inhibitor of AMD-associated inflammation. Furthermore, in addition to administration of Humanin G, knockdown or knock-out of the studied inflammatory markers using siRNA or CRISPR editing, may present a new line of treatment for AMD.”

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 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 media@impactjournals.com.

TP53 Restoration Sensitizes Pancreatic Cancer to Multiple Drugs

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Patients over the age of 50 years old who have been diagnosed with pancreatic cancer have a poorer rate of survival compared to younger patients. This means that pancreatic cancer is a disease associated with aging. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC) and it is frequently diagnosed in its later stages. PDAC is often refractive to chemotherapies and develops resistance to inhibitors and other drugs. Therefore, there is a critical need for researchers to discover novel strategies to overcome drug resistance in PDAC cells.

One potential strategy is to focus on a key gene known for its involvement in many cell processes, including drug resistance and metabolism: TP53. The TP53 gene is often mutated or deleted in cancer cells, which can lead to drug resistance and cancer metastasis. In PDACS, this tumor suppressor gene has been shown to be mutated in 50–75% of patients.

“Many genes have been implicated in PDAC including KRAS, TP53, CDKN2A, SMAD4 and PDGFβR [3, 8, 9, 1822].”

In a new study, researchers—from Brody School of Medicine at East Carolina University, Università di Bologna, University of Parma, and University of Wroclaw—further elucidated TP53’s role in drug resistance in PDAC cells. On April 27, 2022, their research paper was published in Aging (Aging-US) on the cover of Volume 14, Issue 8, and entitled, “Wild type and gain of function mutant TP53 can regulate the sensitivity of pancreatic cancer cells to chemotherapeutic drugs, EGFR/Ras/Raf/MEK, and PI3K/mTORC1/GSK-3 pathway inhibitors, nutraceuticals and alter metabolic properties.”

The Study

In these in vitro studies, the researchers cultured two different PDAC cell lines. One cell line had a gain of function (GOF) TP53 mutation (MIA-PaCa-2) and the other had a loss of TP53 (PANC-28). Both PDAC cell lines also have activating mutations in the KRAS gene. Next, the team introduced either wild-type TP53 (WT-TP53) or a control vector into both PDAC cell lines. Effects from this experiment were analyzed using 26 clinically approved agents.

The chemotherapeutic drugs included: Docetaxel, 5-fluorouracil (5-FU), gemcitabine, Aclacinomycin, Doxorubicin, and Cisplatin. The signal transduction inhibitors included: ARS-1620, PD0325901, LY294002, Pifithrin-μ, 6-bromoindirubin-30-oxime (BIO), SB415286, CHIR99021, Rapamycin, AG1498, Gilteritinib, Sorafenib, OTX008, Tiplaxtinin, Verapamil, and Vismodegib. The natural products included: Cyclopamine, Parthenolide2, Isoliquiritin2, Genistein2, and Daidzein2. The researchers also illustrated the effects of WT-TP53 and mutant TP53 on PDAC cell metabolism with metformin and rapamycin.

“An overview of the effects of WT and mutant TP53 on metabolic properties, together with the effects of metformin and rapamycin, and drugs used to inhibit pancreatic cancer growth, is presented in Figure 16.”

Figure 16. Influences of mutant and WT-TP53 on mitochondrial activity and glucose metabolism and effects of rapamycin and metformin. The effects of WT and mutant TP53 on key enzymes important in glycolysis and how they can influence metabolism and PDAC tumor growth. In our studies, we have examined the effect of GOF mutant TP53 and in some cases WT TP53. In addition, sites of interaction of the type 2 diabetes drug metformin and the immunosuppressive drug rapamycin and their effects on AMPK and mTORC1 are indicated. TP53 can induce mitochondrial apoptosis pathway by regulating the expression of PUMA and other proteins.

The Results

The researchers found that, in the presence of chemotherapeutic drugs, PDAC clonogenicity was decreased by the restoration of WT-TP53. Overall, the restoration of WT-TP53 in PDAC cells increased sensitivity/decreased resistance to various chemotherapeutic drugs, inhibitors and natural products. WT-TP53 also influenced  PDAC cell metabolic properties, including their metabolism. The authors also noted that the activity of mTORC1 (target of rapamycin), which is important in cellular growth and metabolism, can be affected by mutant TP53. They found that GOF mutated TP53 may render PDAC cells more resistant to rapamycin.

“Rapamycin and metformin can interfere with some of the important pathways in the mitochondria, some of which are regulated by TP53 [9698].”

Conclusion

Overall, these results suggest that WT-TP53 can play a key role in PDAC cell sensitivity to multiple drugs used to treat pancreatic cancer. Further studies are needed to better understand the mechanisms underlying the effects of TP53 on drug resistance and metabolism in PDAC cells, as well as its clinical implications.

“Regardless of which of the above processes contributes more to the reduction of mitochondrial metabolism in comparison with the same cells that only express GOF TP53, together the observed changes suggest restoration of WT-TP3 activity confers increased sensitization to various drugs and therapeutic molecules, natural products as well as nutraceuticals.”

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 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 media@impactjournals.com.

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.

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

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: 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.

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

Aging and Circadian Rhythm: Does a Conserved Link Exist?

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 [45]).”

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 JenaFLI Leibniz Institute for Age ResearchJena University HospitalGerman 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

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 media@impactjournals.com.

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