No comments

Targeting Mitophagy as a Therapeutic Strategy for Cancer Treatment

  By

In this new study, researchers investigated the intricate link between mitophagy and cancer stem cells. 

—

Cellular quality control mechanisms like mitophagy, a specialized form of autophagy that eliminates dysfunctional mitochondria, play a pivotal role in various physiological processes. Defects in mitophagy have been linked to neurodegeneration, heart failure, cancer, and aging.

A recent study, by researchers Marta Mauro-Lizcano, Federica Sotgia, and Michael P. Lisanti from the University of Salford, has shed light on the intricate link between mitophagy and cancer stem cells (CSCs). In this study, the researchers developed an innovative fluorescence-based approach to enrich subpopulations of cancer cells exhibiting high basal levels of mitophagy. Their findings reveal that elevated mitophagy activity enhances CSC properties, including self-renewal, ATP production, proliferation, and cell migration, underscoring the potential of targeting mitophagy as a therapeutic strategy for cancer treatment. 

On June 4, 2024, their research paper was published on the cover of Aging’s Volume 16, Issue 11, entitled, “Mitophagy and cancer: role of BNIP3/BNIP3L as energetic drivers of stemness features, ATP production, proliferation, and cell migration.”

“CSCs are responsible for cancer relapse, therapy-resistance, and metastatic dissemination. Therefore, CSC elimination is necessary to prevent cancer recurrence and improve long-term patient outcomes. The search of new targets against CSCs is essential for the success of cancer treatment.” — Mauro-Lizcano et al.

Background

Mitophagy plays a crucial role in maintaining cellular homeostasis by selectively degrading damaged or superfluous mitochondria. This process is governed by specific mitochondrial outer membrane receptors, such as BNIP3 and BNIP3L (also known as NIX), which interact with autophagy-related proteins like LC3/GABARAP to initiate mitophagy. The current study focused on the BNIP3/BNIP3L-dependent pathway, which is rapidly induced under cellular stress conditions like hypoxia and nutrient deprivation.

Cancer stem cells (CSCs) are a subpopulation of cells within a tumor that exhibit stem cell-like properties, such as self-renewal, tumor initiation capability, and drug resistance. These cells are implicated in cancer recurrence, treatment failure, and metastatic dissemination, making their elimination a critical target for effective cancer therapy. Accumulating evidence suggests that mitophagy plays a pivotal role in sustaining CSC properties, including self-renewal, cell propagation, and tumorigenic ability. Consequently, targeting mitophagy has emerged as a promising approach for CSC eradication.

The Study

To investigate the role of mitophagy in CSCs, the researchers developed a novel model system to enrich subpopulations of cancer cells with high basal levels of mitophagy. They employed a BNIP3(L)-promoter-eGFP-reporter system, where the transcriptional activity of BNIP3 and BNIP3L was linked to the expression of enhanced green fluorescent protein (eGFP). This allowed the isolation of cancer cells with high BNIP3/BNIP3L transcriptional activity, indicative of elevated mitophagy levels, using flow cytometry.

The validity of the model was confirmed through various functional assays. Immunoblotting revealed higher protein levels of BNIP3 and BNIP3L in the eGFP-high subpopulations. Additionally, these cells exhibited increased lysosomal mass and mitophagy activity, as measured by flow cytometry using specific probes. Furthermore, the researchers employed the mitochondrially-targeted red fluorescent protein (mt-Keima) to directly visualize and quantify mitophagy, providing further evidence of the model’s robustness.

Stemness & Self-Renewal: Mammosphere Formation Assays

“Mammospheres, or mammary epithelial stem cell aggregates, derived from primary breast tumors or cell lines are thought to develop from rare cancer stem cell (CSC) subpopulations within the tumor.” — Millipore Sigma

To investigate the role of mitophagy in CSC propagation, the researchers compared the mammosphere-forming ability, a functional assay for anchorage-independent growth and self-renewal, between eGFP-high and eGFP-low subpopulations. The eGFP-high cells demonstrated a statistically significant increase in mammosphere formation, indicating enhanced CSC properties. Moreover, these cells exhibited higher levels of CD44, a well-known cell surface marker of CSCs.

To further validate the mammosphere phenotype’s dependence on mitophagy, the researchers treated the eGFP-high and eGFP-low cells with chloroquine, an autophagy inhibitor, and cyclosporin A, a specific mitophagy inhibitor. Interestingly, the eGFP-low subpopulations were more sensitive to both inhibitors, suggesting that the high levels of endogenous mitophagy in the eGFP-high cells conferred resistance to these agents, further reinforcing the functional implication of mitophagy in mammosphere formation.

ATP Production & Mitochondrial Activity

To better understand the effects of mitophagy on CSCs, the researchers analyzed their metabolic profiles. The eGFP-high cells exhibited significantly higher ATP levels compared to eGFP-low cells, despite similar mitochondrial mass. Notably, the eGFP-high cells also demonstrated an increased GSH/GSSG ratio, indicating higher antioxidant capacity and better mitochondrial function.

Proliferation & Cell Cycle Progression

Cell cycle analysis revealed that the eGFP-high cells exhibited a decreased G0/G1 phase and corresponding increases in the S and G2/M phases, suggesting a more proliferative phenotype. This finding aligns with the observed increase in ATP production and mitochondrial activity, supporting the notion that mitophagy contributes to the energetic and proliferative advantages of CSCs.

Drug Resistance: Tamoxifen & Palbociclib

To assess the potential drug resistance phenotype of the eGFP-high and eGFP-low subpopulations, the researchers evaluated their sensitivity to 4-OH-Tamoxifen, an FDA-approved drug for treating estrogen receptor-positive (ER+) breast cancer, and Palbociclib, a CDK4/6 inhibitor. Remarkably, the eGFP-high cells exhibited multi-drug resistance, with significantly higher mammosphere formation compared to the eGFP-low cells upon treatment with these agents, further underscoring the aggressive nature of mitophagy-high CSCs.

Cell Migration and Metastatic Potential

Using the highly metastatic MDA-MB-231 breast cancer cell line, the researchers investigated the migratory capacity of the eGFP-high and eGFP-low subpopulations. Consistent with the observed stemness and metabolic advantages, the eGFP-high MDA-MB-231 cells exhibited higher levels of cell migration, suggesting that elevated mitophagy contributes to the metastatic potential of CSCs.

Therapeutic Implications & Future Directions

“In summary, our current work has provided a novel strategy to enrich for a sub-population of cancer cells, with high basal levels of mitophagy.” — Mauro-Lizcano et al.

The findings of this study highlight the critical role of mitophagy in driving various hallmarks of CSCs, including self-renewal, ATP production, proliferation, and cell migration. By targeting mitophagy, particularly the BNIP3/BNIP3L-dependent pathway, researchers may be able to develop novel therapeutic strategies for eliminating CSCs and improving patient outcomes in cancer treatment.

Future research should focus on exploring the molecular mechanisms underlying the observed effects of mitophagy on CSC properties and identifying specific mitophagy inhibitors or modulators with potential therapeutic applications. Additionally, further investigation into the interplay between mitophagy and other cellular processes, such as metabolic reprogramming and signaling pathways, could provide valuable insights into the complex biology of CSCs and pave the way for more effective targeted therapies.

Conclusion

The study by Mauro-Lizcano et al. represents a significant advancement in our understanding of the role of mitophagy in cancer stem cell biology. By developing an innovative model system and employing a multifaceted approach, the researchers have unveiled the energetic drivers and functional implications of mitophagy in stemness features, ATP production, proliferation, and cell migration. These findings not only deepen our knowledge of the intricate mechanisms governing CSC behavior but also highlight the potential of targeting mitophagy as a promising therapeutic strategy for combating cancer recurrence, treatment resistance, and metastatic dissemination.

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.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

Werner Syndrome and the Power of Proteomics

  By

In this new study, researchers used proteomics to investigate Werner syndrome and proteins associated with age and/or genotype in the serum and liver of mice.

—

Werner syndrome (WS) is a rare genetic disorder marked by the premature onset of features typically associated with normal aging. This autosomal recessive condition manifests in individuals who generally develop normally until adolescence. As the syndrome progresses, affected individuals are predisposed to age-related diseases much earlier in life. These conditions include cataracts, type 2 diabetes, atherosclerosis, osteoporosis, and various cancers. The underlying cause of Werner syndrome is believed to be mutations in the WRN gene, which encodes a RecQ helicase crucial for DNA repair and replication.

Despite the accelerated aging, cognitive function remains unaffected in individuals with WS, providing a unique model for studying the mechanisms of aging and exploring potential therapeutic interventions. Although extensive research has been conducted, the precise mechanisms underlying these effects remain elusive.

On May 24, 2024, researchers Lucie Aumailley, Marie Julie Dubois, André Marette, and Michel Lebel from Université Laval published a new research paper chosen as the cover of Aging’s Volume 16, Issue 10, entitled, “Integrated liver and serum proteomics uncover sexual dimorphism and alteration of several immune response proteins in an aging Werner syndrome mouse model.” Recognizing the limitations of traditional investigative approaches, Aumailley et al. utilized advanced proteomics in their study. Proteomics allows the simultaneous identification and quantification of hundreds of proteins, providing a comprehensive analysis of liver and serum proteome profiles from wild-type and WRN mutant mice at different ages to uncover biological processes influenced by age and genotype.

“Proteomics analysis at different ages allows us to follow the progressive biological alterations (including histological fat accumulation) in the liver according to age and/or the Wrn genotype.”

Key Findings: Sexual Dimorphism & Immune Response

“The major goal of this study was to look at murine hepatic proteomic profiles at two different time points and determine the impact of a mutation in the Wrn gene product with age in the liver of mice.”

The study’s most compelling discovery was the significant sexual dimorphism in liver tissue and serum proteome profiles, regardless of age or genotype. Principal component analysis (PCA) revealed distinct clustering patterns, indicating fundamental differences in protein expression between male and female mice. This highlights the importance of considering sex in biomedical research due to its potential impact on disease progression and treatment responses. 

Additionally, the research unveiled an enrichment of proteins involved in immune responses, particularly in the liver tissue of WRN mutant mice. Elevated levels of specific immunoglobulin variants (Igkc, Ighm, and Igkv5-39) in aged WRN mutant mice suggest a link to fatty liver progression in WS. Both sexes exhibited fatty liver; however, aged male WRN mutant mice showed significant upregulation of proteins involved in lipid and fatty acid metabolism, exacerbating age-related fat accumulation in the liver. Increased proteins related to oxidant detoxification processes in male WRN mutant mice indicated a heightened cellular antioxidant response, aligning with oxidative stress’s role in aging.

Implications & Future Directions

Several proteins altered in aged WRN mutant mice, such as A1bg, Vnn1, and Serpina1e, have been linked to chronic liver diseases in humans, emerging as potential biomarkers for disease progression. These findings offer insights for future diagnostic and therapeutic strategies. The study’s robust experimental design and rigorous analytical approaches, including label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS), PCA, hierarchical clustering, and gene ontology enrichment analyses, lend credibility to its findings. 

Future research should address limitations such as broader age ranges, tissue specificity, and functional validation to build on these findings. The study underscores the importance of considering sex in biomedical research and opens new avenues for exploring protein alterations as biomarkers or therapeutic targets, potentially improving diagnosis, disease monitoring, and personalized treatment strategies for WS and related age-associated disorders.

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.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

When Does Human Life Truly Begin?

  By

In this fascinating new review, researchers Polina A. Loseva and Vadim N. Gladyshev discuss “The beginning of becoming a human.”

—

For centuries, the question of when human life commences has perplexed philosophers, theologians, and scientists alike. With the advent of modern reproductive technologies and groundbreaking scientific advancements, this profound inquiry has taken on renewed urgency and complexity. In a fascinating new review paper, researchers Polina A. Loseva and Vadim N. Gladyshev from Harvard Medical School delved into this intricate subject, exploring the multifaceted perspectives that have shaped our understanding of life’s origins. On May 6, 2024, their review was published on the cover of Aging’s Volume 16, Issue 9, entitled, “The beginning of becoming a human.” Below, this article breaks down their chronological review of the various ways life has been defined: movement, fusion, self-sufficiency, uniqueness, and now, aging.

Life Defined by Movement: The Quickening

Historically, the notion of life’s inception was inextricably linked to the first perceptible movements of the fetus within the womb, a phenomenon known as “quickening.” In 18th-century England, this milestone was so pivotal that it could even pardon a pregnant woman sentenced to hanging. However, as our comprehension of embryonic development deepened, it became evident that quickening is an unreliable indicator, as the timing varies widely among individuals and is largely dependent on maternal factors.

Life Defined by Fusion: The Conception Conundrum

Another perspective posits that life begins at the moment of conception, when the egg and sperm fuse, forming a unique genetic entity distinct from its progenitors. However, this definition encounters challenges, as the newly formed zygote lacks a fully assembled nucleus and functional genome initially. Furthermore, the ability to split or combine embryos during the early stages raises philosophical quandaries about the individuality and uniqueness of life.

Life Defined by Self-Sufficiency: Viability and Technological Advancement

As medical technologies advanced, the definition of life’s beginning shifted towards the point at which the fetus could theoretically survive outside the womb, albeit with medical intervention. This threshold, known as “viability,” has been a moving target, continually redefined as neonatal care capabilities improve. However, with the advent of artificial womb systems, this criterion may become increasingly ambiguous.

In the midst of the heated debates surrounding reproductive technologies and embryonic experimentation in the 1980s, the Warnock Committee was tasked with establishing ethical boundaries. Their landmark report introduced the “14-day rule,” a compromise that prohibited the cultivation or experimentation on human embryos beyond 14 days after fertilization. While the rationale behind this specific timeframe was somewhat arbitrary, it struck a delicate balance between scientific progress and ethical considerations.

Life Defined by Uniqueness: The Gastrulation Milestone

Remarkably, the 14-day stage coincides with a pivotal developmental event known as gastrulation, during which the embryo transitions from a single-layered structure to a three-layered disc that prefigures the body plan of a vertebrate organism. This transformation not only establishes the embryo’s anterior-posterior, dorsal-ventral, and left-right axes but also marks the point at which the embryo becomes increasingly resistant to splitting or combining, solidifying its individuality.

As scientific capabilities advanced, the ability to culture human embryos beyond the 14-day threshold became a reality, reigniting discussions about revising the Warnock Committee’s guidelines. Proponents argued that this boundary was arbitrary and that our improved understanding of neural development warranted an extension. Others proposed alternative timeframes, such as 22 days (when the nervous system begins to form) or 28 days (when abortions are typically not performed). Ultimately, the International Society for Stem Cell Research (ISSCR) opted for a case-by-case approach, with individual oversight committees evaluating each experiment’s merits.

Life Defined by Aging: A Paradigm Shift

Intriguingly, recent studies have shed light on an overlooked aspect of embryonic development: the onset of aging. By employing epigenetic clocks and other molecular biomarkers, researchers have discovered that the “ground zero” point of aging coincides remarkably with the 14-day stage, marking the transition from a rejuvenated state to the commencement of the aging process. This finding not only reinforces the significance of this developmental milestone but also prompts a reconsideration of life’s beginnings from the perspective of aging trajectories.

The 14++ Conundrum: Navigating Ethical and Scientific Imperatives

As the debate surrounding the 14-day rule continues to evolve, a paradoxical situation has emerged: the scientific consensus on the beginning of life remains elusive, while the ethical boundaries are subject to ongoing reevaluation and case-by-case determinations. This dichotomy underscores the need for a broader discussion involving not only embryologists but also bioethicists, legal experts, and diverse societal stakeholders.

Rather than seeking a definitive answer to the question of when human life begins, a more holistic approach may be to consider the emergence of different levels of life organization during embryonic development. These levels could encompass the cellular, organismal, and human life levels, each with its own unique characteristics and potential boundaries. By recognizing the complexity and multidimensionality of this process, we may gain a deeper appreciation for the intricate tapestry that weaves together the beginnings of human existence.

Synthetic Embryos: Witnessing the Emergence of Life In Vitro

While the 14-day stage may not represent the ultimate boundary for human life, it emerges as a compelling candidate for the transition to organismal life. At this juncture, the embryo exhibits signs of self/non-self discrimination, with cells organized into layers that prefigure the body plan. Concurrently, the rejuvenation processes conclude, and the aging trajectory commences for the somatic cells. This confluence of events suggests that the 14-day stage marks the emergence of a living organism, even if it may not yet possess all the attributes of a human being.

Recent breakthroughs in the generation of synthetic embryos, or “embryoids,” from pluripotent stem cells have opened up unprecedented opportunities to witness the emergence of organismal life in vitro. By recapitulating the early stages of human development, including gastrulation and the formation of embryonic layers, these synthetic models offer a unique window into the intricate processes underlying the transition from a collection of cells to an organized, living entity.

The Path Forward: Embracing Complexity and Collaboration

As we continue to unravel the enigma of life’s beginnings, it is evident that a multidisciplinary approach is essential. Collaboration among embryologists, bioethicists, legal scholars, and diverse stakeholders will be crucial in navigating the ethical and scientific complexities that arise. By embracing the nuances and respecting the perspectives of various disciplines, we can collectively chart a course that harmonizes scientific progress with ethical considerations, ultimately deepening our understanding of the profound journey that culminates in the emergence of a human being.

Click here to read the full review 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.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

UV-A Exposure, Cellular Senescence, and Vision Impairment

  By

In this new study, researchers investigated the senescent phenotypes of human corneal endothelial cells upon UV-A exposure.

—

With an ever-increasing global population grappling with age-related ocular ailments like cataracts, dry eyes, glaucoma, and macular degeneration, the need for new research in this domain is more pressing than ever. 

In a new study, researchers Kohsaku Numa, Sandip Kumar Patel, Zhixin A. Zhang, Jordan B. Burton, Akifumi Matsumoto, Jun-Wei B. Hughes, Chie Sotozono, Birgit Schilling, Pierre-Yves Desprez, Judith Campisi (1948-2024), and Koji Kitazawa from the Buck Institute for Research on Aging, Kyoto Prefectural University of Medicine, University of Cambridge, and California Pacific Medical Center shed light on a pivotal aspect of corneal health – the impact of ultraviolet-A (UV-A) radiation on corneal endothelial cells. Their research paper was published on the cover of Aging’s Volume 16, Issue 8, entitled, “Senescent characteristics of human corneal endothelial cells upon ultraviolet-A exposure.”

“The objective of this study was to investigate the senescent phenotypes of human corneal endothelial cells (hCEnCs) upon treatment with ultraviolet (UV)-A.”

Corneal Health & Cellular Senescence

The cornea, a transparent tissue responsible for refracting incoming light onto the retina, plays a crucial role in our visual acuity. Its transparency is maintained by a single layer of cells called corneal endothelial cells (CEnCs), which cover the posterior surface. However, these cells possess a limited capacity for proliferation, rendering them susceptible to pathological cell loss, potentially leading to corneal endothelial dysfunction and, ultimately, visual impairment or blindness.

Current treatments for CEnC dysfunction include corneal endothelial transplantation using donor corneas and cell injection therapy utilizing cultured human CEnCs (hCEnCs). Nonetheless, pathological CEnC loss persists even after successful interventions, culminating in graft failure. To combat this, researchers have delved into the intricate mechanisms underlying hCEnCs loss, uncovering a potential link between corneal endothelial disease and cellular senescence.

While cellular senescence acts as a natural defense mechanism against uncontrolled cell proliferation, the accumulation of senescent cells can exacerbate pathological conditions and contribute to various age-related etiologies. Notably, senescent cells acquire an inflammatory phenotype known as the senescence-associated secretory phenotype (SASP), which can adversely alter the surrounding microenvironment over time.

The Study

In the current study, the researchers exposed hCEnCs to varying doses of UV-A radiation, ranging from 0 J/cm2 (mock) to 20 J/cm2. Cells treated with 10 Gy of ionizing radiation (IR) served as positive controls for senescence induction.

“UV-A accounts for about 90% of the UV radiation reaching the earth’s surface and is known to induce ROS causing oxidative stress [34]. Oxidative stress causes molecular alternation, leading to cellular senescence [35]. Observations of UV-A intensity suggest that exposure to 5 J/cm2 of UV-A is roughly equivalent to one hour of noonday sun exposure during the summer [34].”

Through a meticulous analysis of cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation, and expression of senescence markers (p16 and p21), the team identified that hCEnCs exposed to 5 J/cm2 of UV-A exhibited typical senescent phenotypes, including enlargement, increased SA-β-gal activity, decreased cell proliferation, and elevated expression of p16 and p21. The researchers employed RNA sequencing (RNA-Seq) and proteomics analysis to gain a comprehensive understanding of the senescence response in hCEnCs. 

Results

RNA-Seq analysis revealed a significant overlap in the pathways modulated by UV-A and IR-induced senescence. Upregulated genes were enriched in pathways associated with extracellular matrix (ECM) organization, cellular component movement, response to cytokines, cell migration, and motility – processes intimately linked to corneal endothelial diseases.

Interestingly, while the number of significantly up- or down-regulated genes differed between UV-A and IR exposure, the proteomics analysis revealed a much smaller disparity in the number of altered proteins, suggesting that UV-A might be a more physiologically relevant method for inducing cellular senescence in hCEnCs. The proteomics analysis unveiled a wealth of information regarding the SASP of UV-A-induced senescent hCEnCs. Key SASP components, including STC1, GDF15, C7, C9, SERPINE2, and PDGFA, were identified among the top 40 secreted proteins.

The researchers also detected elevated levels of CXCL1, CXCL8, MMP2, COL6A2, COL8A1, COL12A1, and other proteins previously reported as SASP factors in various cell types. Notably, proteins associated with glycolysis, such as SLC2A1, GPI, ENO1, PKM, TPI1, and LDH, were also found to be significantly upregulated.

Conclusions & Future Directions

“Here, we showed that cellular senescence is induced in hCEnCs upon UV-A irradiation and conducted comprehensive analyses of RNA and protein expression.”

This study not only sheds light on the senescent characteristics of hCEnCs upon UV-A exposure but also highlights the potential role of cellular senescence in the pathogenesis of corneal endothelial diseases. By identifying the overlapping pathways and SASP factors modulated by both UV-A and IR-induced senescence, the researchers have paved the way for a deeper understanding of the molecular mechanisms underlying CEnC dysfunction.

Furthermore, the identification of specific proteins associated with corneal endothelial diseases, such as TGFBI, TGFB1, TGFB2, LOXL1, LOXL2, and complement factors, provides valuable insights into potential therapeutic targets and biomarkers for early detection and intervention.

As the research community continues to unravel the enigma of cellular senescence and its implications in ocular health, this study stands as a testament to the power of multidisciplinary approaches and cutting-edge techniques in advancing our understanding of age-related vision impairment.

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.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

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

  By

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

—

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

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

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

The Study

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

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

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

Methodology & Data Sources

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

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

Key Findings

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

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

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

Implications & Future Directions

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

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

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

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

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

—

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

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

How Menopause Changes Brain Structure and Connectivity

  By

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.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

Predicting Brain Age With Machine Learning and Transcriptome Profiling

  By

In this study, researchers investigated age-associated gene expression changes in the prefrontal cortex of male and female brains and used machine learning to develop age prediction models.

—

The human brain is a complex organ, and its aging process is influenced by a plethora of factors, both genetic and environmental. Aging-related changes in the brain can lead to cognitive decline and susceptibility to neurodegenerative diseases. Therefore, understanding the molecular mechanisms underlying these changes is crucial for developing therapeutic strategies to delay or prevent age-related cognitive decline.

Over the past few years, a myriad of scientific studies have been conducted to understand the intricate relationship between our genes and the aging process. In a new study, researchers Joseph A. Zarrella and Amy Tsurumi from Harvard T.H. Chan School of Public Health, Massachusetts General Hospital, Harvard Medical School, and Shriner’s Hospitals for Children-Boston explored the concept of genome brain age prediction, a groundbreaking area of study that employs advanced bioinformatics tools to analyze changes in gene expression associated with aging. On February 28, 2024, their research paper was published and chosen as the cover paper for Aging’s Volume 16, Issue 5, entitled, “Genome-wide transcriptome profiling and development of age prediction models in the human brain.”

“[…] we aimed to profile transcriptome changes in the aging PFC [prefrontal cortex] overall and compare females and males, and develop prediction models for age.”

Transcriptome Profiling in the Prefrontal Cortex

The prefrontal cortex (PFC) plays a significant role in the aging process. It is responsible for a host of cognitive functions, including decision-making and planning. Throughout the aging process, significant transcriptome alterations occur in the PFC compared to other regions of the brain. These alterations can influence cognitive decline and susceptibility to neurodegenerative diseases.

Delving deeper into the complexities of aging, researchers have turned to transcriptome profiling as a powerful tool to uncover the molecular changes occurring within the prefrontal cortex. Transcriptome profiling allows scientists to measure the expression levels of all genes in a cell or tissue. By analyzing the transcriptome of the PFC, researchers can identify genes that are differentially expressed during the aging process. These genes can serve as potential biomarkers for age prediction.

The Study

In their groundbreaking research, Zarrella and Tsurumi aimed to develop prediction models for age based on the expression levels of specific panels of transcripts in the PFC. They leveraged advanced machine learning algorithms, including the least absolute shrinkage and selection operator (Lasso), Elastic Net (EN), eXtreme Gradient Boosting (XGBoost), and Light Gradient Boosting Machine (LightGBM), to develop accurate prediction models for chronological age.

The researchers used postmortem PFC transcriptome datasets obtained from the Gene Expression Omnibus (GEO) repository, ranging in age from 21 to 105 years. They identified differentially regulated transcripts in old and elderly samples compared to young samples and assessed the genes associated with age using ontology, pathway, and network analyses.

Machine learning algorithms were used to develop accurate prediction models for chronological age based on the expression levels of specific transcripts. The study found that specific gene expression changes in the PFC are highly correlated with age. Some transcripts showed female and male-specific differences, indicating that sex may play a role in the aging process at the molecular level.

Key Findings & Implications

The study identified several key genes whose expression levels change significantly with age. These genes include Carbonic Anhydrase 4 (CA4), Calbindin 1 (CALB1), Neuropilin and Tolloid Like 2 (NETO2), and Olfactomedin1 (OLFM1), among others. Many of these genes have been previously implicated in aging or aging-related diseases, validating the results of this study.

The researchers also developed four highly accurate age prediction models using different machine learning algorithms. These models were validated in a test set and an external validation set, demonstrating their potential application in predicting chronological age based on gene expression levels.

“Our results support the notions that specific gene expression changes in the PFC are highly correlated with age, that some transcripts show female and male-specific differences, and that machine learning algorithms are useful tools for developing prediction models for age based on transcriptome information.”

Conclusions & Future Directions

This study sheds light on the complex relationship between gene expression changes and the aging process in the human brain. The findings underscore the potential of using transcriptome profiling and machine learning algorithms for age prediction. The identified genes could serve as potential biomarkers for age prediction and may offer new insights into the molecular mechanisms underlying the aging process.

However, further validation of these models in larger populations and molecular studies to elucidate the potential mechanisms by which the identified transcripts may be related to aging phenotypes would be beneficial. Additionally, more inclusive studies investigating the interplay between genetic markers and factors such as sex, lifestyle, and environmental exposures are warranted.

In conclusion, this study provides a promising foundation for future research on genome brain age prediction. It also underscores the potential of transcriptome profiling and machine learning for exploring the complex interplay between our genes and the aging process. This approach could pave the way for personalized medicine strategies aimed at preventing or delaying age-related cognitive decline and neurodegenerative diseases.

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.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

Overcoming Missing Data in the Swedish National Study on Aging

  By

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

—

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

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

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

Setting the Context

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

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

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

What is Multiple Imputation?

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

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

The Study

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

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

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

Conclusions

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

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

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

—

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

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

Aging’s Top 10 Papers in 2023 (Crossref Data)

  By

Crossref is a non-profit organization that logs and updates citations for scientific publications. Each month, Crossref identifies a list of the most popular Aging (Aging-US) papers based on the number of times a DOI is successfully resolved. 

Below are Crossref’s Top 10 Aging DOIs in 2023.

#10: Old-age-induced obesity reversed by a methionine-deficient diet or oral administration of recombinant methioninase-producing Escherichia coli in C57BL/6 mice

DOI: https://doi.org/10.18632/aging.204783

Authors: Yutaro Kubota, Qinghong Han, Jose Reynoso, Yusuke Aoki, Noriyuki Masaki, Koya Obara, Kazuyuki Hamada, Michael Bouvet, Takuya Tsunoda, and Robert M. Hoffman

Institutions: AntiCancer Inc., University of California San Diego and Showa University School of Medicine 

Quote: “This is the first report that showed the efficacy of methionine restriction to reverse old-age-induced obesity.”

#9: Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity

DOI: https://doi.org/10.18632/aging.204498 

Authors: Pedro S. Marra, Takehiko Yamanashi, Kaitlyn J. Crutchley, Nadia E. Wahba, Zoe-Ella M. Anderson, Manisha Modukuri, Gloria Chang, Tammy Tran, Masaaki Iwata, Hyunkeun Ryan Cho, and Gen Shinozaki

Institutions: Stanford University School of Medicine, University of Iowa, Tottori University Faculty of Medicine, University of Nebraska Medical Center College of Medicine, and Oregon Health and Science University School of Medicine 

Quote: “In this study, we compared genome-wide DNA methylation rates among metformin users and nonusers […]”

#8: Age prediction from human blood plasma using proteomic and small RNA data: a comparative analysis

DOI: https://doi.org/10.18632/aging.204787 

Authors: Jérôme Salignon, Omid R. Faridani, Tasso Miliotis, Georges E. Janssens, Ping Chen, Bader Zarrouki, Rickard Sandberg, Pia Davidsson, and Christian G. Riedel

Institutions: Karolinska Institutet, University of New South Wales, Garvan Institute of Medical Research, and AstraZeneca

Quote: “[…] we see our work as an indication that combining different molecular data types could be a general strategy to improve future aging clocks.”

#7: Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic

DOI: https://doi.org/10.18632/aging.204616 

Authors: Fares Al-Mansour, Abdullah Alraddadi, Buwei He, Anes Saleh, Marta Poblocka, Wael Alzahrani, Shaun Cowley, and Salvador Macip

Institutions: University of Leicester, Najran University and Universitat Oberta de Catalunya

Quote: “The mechanisms of induction of senescent cell death by CUDC-907 remain to be fully elucidated.”

#6: Potential reversal of biological age in women following an 8-week methylation-supportive diet and lifestyle program: a case series

DOI: https://doi.org/10.18632/aging.204602 

Authors: Kara N. Fitzgerald, Tish Campbell, Suzanne Makarem, and Romilly Hodges

Institutions: Institute for Functional Medicine, Virginia Commonwealth University and the American Nutrition Association

Quote: “[…] these data suggest that a methylation-supportive diet and lifestyle intervention may favorably influence biological age in both sexes during middle age and older.”

#5: Leukocyte telomere length, T cell composition and DNA methylation age

DOI: https://doi.org/10.18632/aging.101293 

Authors: Brian H. Chen, Cara L. Carty, Masayuki Kimura, Jeremy D. Kark, Wei Chen, Shengxu Li, Tao Zhang, Charles Kooperberg, Daniel Levy, Themistocles Assimes, Devin Absher, Steve Horvath, Alexander P. Reiner, and Abraham Aviv

Institutions: National Institute on Aging, National Heart, Lung and Blood Institute, George Washington University, Children’s National Medical Center, Rutgers State University of New Jersey, Hebrew University-Hadassah School of Public Health and Community Medicine, Tulane University, Fred Hutchinson Cancer Research Center, Stanford University School of Medicine, HudsonAlpha Institute for Biotechnology, University of California LA, and University of Washington

Quote: “The two key observations of this study are: (a) LTL is inversely correlated with EEAA; and (b) the LTL-EEAA correlation largely reflects the proportions of imputed naïve and memory CD8+ T cell populations in the leukocytes from which DNA was extracted.”

#4: DNA methylation GrimAge strongly predicts lifespan and healthspan

DOI: https://doi.org/10.18632/aging.101684 

Authors: Ake T. Lu, Austin Quach, James G. Wilson, Alex P. Reiner, Abraham Aviv, Kenneth Raj, Lifang Hou, Andrea A. Baccarelli, Yun Li, James D. Stewart, Eric A. Whitsel, Themistocles L. Assimes, Luigi Ferrucci, and Steve Horvath

Institutions: University of California LA, University of Mississippi Medical Center, Fred Hutchinson Cancer Research Center, Rutgers State University of New Jersey, Public Health England, Northwestern University Feinberg School of Medicine, Columbia University Mailman School of Public Health, University of North Carolina, Chapel Hill, Stanford University School of Medicine, VA Palo Alto Health Care System, and National Institutes of Health 

Quote: “We coin this DNAm-based biomarker of mortality “DNAm GrimAge” because high values are grim news, with regards to mortality/morbidity risk. Our comprehensive studies demonstrate that DNAm GrimAge stands out when it comes to associations with age-related conditions, clinical biomarkers, and computed tomography data.”

#3: Deep biomarkers of aging and longevity: from research to applications

DOI: https://doi.org/10.18632/aging.102475 

Authors: Alex Zhavoronkov, Ricky Li, Candice Ma, and Polina Mamoshina

Institutions: Insilico Medicine, The Buck Institute for Research on Aging, The Biogerontology Research Foundation, Sinovation Ventures, Sinovation AI Institute, and Deep Longevity, Ltd

Quote: “Here we present the current state of development of the deep aging clocks in the context of the pharmaceutical research and development and clinical applications.”

#2: An epigenetic biomarker of aging for lifespan and healthspan

DOI: https://doi.org/10.18632/aging.101414 

Authors: Morgan E. Levine, Ake T. Lu, Austin Quach, Brian H. Chen, Themistocles L. Assimes, Stefania Bandinelli, Lifang Hou, Andrea A. Baccarelli, James D. Stewart, Yun Li, Eric A. Whitsel, James G Wilson, Alex P Reiner, Abraham Aviv, Kurt Lohman, Yongmei Liu, Luigi Ferrucci, and Steve Horvath

Institutions: University of California LA, National Institute on Aging, Stanford University School of Medicine, Azienda Toscana Centro, Northwestern University Feinberg School of Medicine, Columbia University Mailman School of Public Health, University of North Carolina, Chapel Hill, University of Mississippi Medical Center, Fred Hutchinson Cancer Research Center, Rutgers State University of New Jersey, and Wake Forest School of Medicine

Quote: “Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.”

#1: Chemically induced reprogramming to reverse cellular aging

DOI: https://doi.org/10.18632/aging.204896

Authors: Jae-Hyun Yang, Christopher A. Petty, Thomas Dixon-McDougall, Maria Vina Lopez, Alexander Tyshkovskiy, Sun Maybury-Lewis, Xiao Tian, Nabilah Ibrahim, Zhili Chen, Patrick T. Griffin, Matthew Arnold, Jien Li, Oswaldo A. Martinez, Alexander Behn, Ryan Rogers-Hammond, Suzanne Angeli, Vadim N. Gladyshev, and David A. Sinclair

Institutions: Harvard Medical School, University of Maine and Massachusetts Institute of Technology (MIT) 

Quote: “We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.”

—

Click here to read the latest papers published by Aging.

—

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

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

No comments

Senescence-Related TME Genes as Key Prognostic Predictors in HNSCC

  By

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

—

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

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

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

The Study

Identification of Prognostic Senescence-Related TME Genes

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

Senescence-Related TME Subtypes and Characterization

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

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

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

Risk Scoring Based on Senescence-Related TME Status

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

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

Immunotherapy Response Prediction and Single-Cell Analysis

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

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

Conclusion

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

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

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

—

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

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

  • Follow Us