A new research paper was published on the cover of Aging (Aging-US) Volume 15, Issue 6, entitled, “Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail.”

Aging coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence-associated secretory phenotype, but the relationship of senescent cells to muscle atrophy is unclear. Previously, researchers found that a metformin + leucine (MET+LEU) treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. 

In this new study, researchers Jonathan J. Petrocelli, Naomi M.M.P. de Hart, Marisa J. Lang, Elena M. Yee, Patrick J. Ferrara, Dennis K. Fix, Amandine Chaix, Katsuhiko Funai, and Micah J. Drummond from the University of Utah aimed to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. 

“The purpose of this study was to identify the skeletal muscle cell-intrinsic effects of MET+LEU during an atrophy stimulus. Secondarily, we sought to determine the possible mechanisms underlying MET+LEU action on skeletal muscle cells with an emphasis on cellular senescence.”

C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during atrophy. Additionally, aged mouse single myofibers and older human donor primary myoblasts were individually isolated to determine the translational potential of MET+LEU on muscle cells. MET+LEU (25 + 125 μM) treatment increased myotube differentiation and prevented myotube atrophy. Low concentration (0.1 + 0.5 μM) MET+LEU had unique effects to prevent muscle atrophy and increase transcripts related to protein synthesis and decrease transcripts related to protein breakdown. Myotube atrophy resulted in dysregulated proteostasis that was reversed with MET+LEU and individually with proteasome inhibition (MG-132). 

Inflammatory and cellular senescence transcriptional pathways and respective transcripts were increased following myotube atrophy yet reversed with MET+LEU treatment. Dasatinib + quercetin (D+Q) senolytic prevented myotube atrophy similar to MET+LEU. Finally, MET+LEU prevented loss in myotube size in alternate in vitro models of muscle atrophy as well as in aged myofibers while, in human primary myotubes, MET+LEU prevented reductions in myonuclei fusion. These data support that MET+LEU has skeletal muscle cell-autonomous properties to prevent atrophy by reversing senescence and improving proteostasis.

“In conclusion, this study provides evidence of a possible link between cellular senescence and disrupted proteostasis that is targeted by MET+LEU in muscle cells to reverse the muscle atrophy phenotype.”

DOI: https://doi.org/10.18632/aging.204600 

Corresponding Author: Micah J. Drummond - micah.drummond@hsc.utah.edu 

Keywords: skeletal muscle atrophy, inflammation, senolytic, AMPK, protein breakdown

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Aging (Aging-US)

Metformin & Leucine Prevent Cellular Senescence & Proteostasis Disruption

A new research paper was published on the cover of Aging (Aging-US) Volume 15, Issue 7, entitled, “p21 facilitates chronic lung inflammation via epithelial and endothelial cells.”

Cellular senescence is a stable state of cell cycle arrest that regulates tissue integrity and protects the organism from tumorigenesis. However, the accumulation of senescent cells during aging contributes to age-related pathologies. One such pathology is chronic lung inflammation. 

p21 (CDKN1A) regulates cellular senescence via inhibition of cyclin-dependent kinases (CDKs). However, its role in chronic lung inflammation and functional impact on chronic lung disease, where senescent cells accumulate, is less understood. In this new study, researchers Naama Levi, Nurit Papismadov, Julia Majewska, Lior Roitman, Noa Wigoda, Raya Eilam, Michael Tsoory, Ron Rotkopf, Yossi Ovadya, Hagay Akiva, Ofer Regev, and Valery Krizhanovsky from the Weizmann Institute of Science aimed to elucidate the role of p21 in chronic lung inflammation.

“[...] we subjected p21 knockout (p21-/-) mice to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to chronic bronchitis and accumulation of senescent cells.” 

The researchers utilized a lipopolysaccharide (LPS) inhalation-induced chronic bronchitis procedure to study the effects of repetitive LPS exposure on p21 knockout (p21-/-) mice. Furthermore, the team aimed to examine the specific contribution of the epithelial, endothelial and immune compartments to chronic bronchitis pathology. They found that p21 knockout led to a reduced presence of senescent cells, alleviated the pathological manifestations of chronic lung inflammation, and improved the fitness of the mice. The expression profiling of the lung cells revealed that resident epithelial and endothelial cells, but not immune cells, play a significant role in mediating the p21-dependent inflammatory response following chronic LPS exposure. 

“Therefore, we suggest that p21-dependent elimination of senescent cells may limit the damage induced by the pro-inflammatory presence of senescent cells, but also promote tissue regeneration. Therefore, inhibition of p21 represents a promising strategy for limiting age-related inflammatory disorders in general and obstructive lung diseases in particular.”

DOI: https://doi.org/10.18632/aging.204622 

Corresponding Author: Valery Krizhanovsky - valery.krizhanovsky@weizmann.ac.il 

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Keywords - aging, cellular senescence, chronic lung inflammation, p21 (CDKN1A)

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Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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p21 facilitates chronic lung inflammation via epithelial and endothelial cells

p21 Facilitates Chronic Lung Inflammation via Epithelial and Endothelial Cells

A new research paper was published in Aging (Aging-US) Volume 15, Issue 7, entitled, “Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.”

The accumulation of senescent cells has an important role in the phenotypical changes observed in aging and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. 

Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated. 

Given the involvement of HDACs and the PI3K pathway in senescence, researchers Fares Al-Mansour, Abdullah Alraddadi, Buwei He, Anes Saleh, Marta Poblocka, Wael Alzahrani, Shaun Cowley, and Salvador Macip from the University of Leicester, Najran University and Universitat Oberta de Catalunya hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. 

“Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.” 

Consistent with this, CUDC-907 showed senolytic properties in different models of stress-induced senescence. Their results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, their results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved.

“According to our results, CUDC-907 could be an interesting drug to be used as a senolytic, alone or as part of a targeted approach.”

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

Corresponding author - Salvador Macip - sm460@le.ac.uk

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Keywords - aging, senescence, senolytics, HDAC, PI3K, CUDC-907

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Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Characterization of the HDAC/PI3K Inhibitor CUDC-907 as a Novel Senolytic

A new research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 8, entitled, “A chronic wound model to investigate skin cellular senescence.”

Wound healing is an essential physiological process for restoring normal skin structure and function post-injury. The role of cellular senescence, an essentially irreversible cell cycle state in response to damaging stimuli, has emerged as a critical mechanism in wound remodeling. Transiently-induced senescence during tissue remodeling has been shown to be beneficial in the acute wound healing phase. In contrast, persistent senescence, as observed in chronic wounds, contributes to delayed closure. 

In this new study, researchers Saranya P. Wyles, Parisa Dashti, Tamar Pirtskhalava, Burak Tekin, Christina Inman, Lilian Sales Gomez, Anthony B. Lagnado, Larissa Prata, Diana Jurk, João F. Passos, Tamar Tchkonia, and James L. Kirkland from the Mayo Clinic in Rochester, Minnesota, describe a chronic wound murine model and its cellular senescence profile, including the senescence-associated secretory phenotype.

“Herein we hypothesize that persistent senescent cell accumulation contributes to delayed healing in chronic wounds.” 

This study presents a novel oxidative stress-induced chronic murine wound mouse model in which there is capacity to target aberrant senescent cell expression. Pharmacological manipulation of oxidative stress can influence wound healing and result in delayed wound closure, which offers the opportunity to characterize cellular senescence in late stages of wound healing. The molecular and histological profiles of senescent cells in the epidermis and dermis demonstrate the adverse influence of SASP factors in the chronic wound bed, a new avenue for root-cause, targeted therapeutic interventions.

“To our knowledge, this study is the first chronic wound murine model to profile the effects of the chronic cellular senescence that is linked to delayed wound healing. This may have implications for developing interventions that target cellular senescence for chronic or stalled wounds as a root cause-driven therapeutic strategy.”

DOI: https://doi.org/10.18632/aging.204667 

Corresponding Authors: James L. Kirkland - kirkland.james@mayo.edu, and Tamar Tchkonia - tchkonia.tamar@mayo.edu

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Keywords - aging, wound healing, cellular senescence, chronic wound, re-epithelization, skin

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Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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A Chronic Wound Model to Investigate Skin Cellular Senescence

A new research paper was published in Aging (Aging-US) Volume 15, Issue 8, entitled, “Single-cell transcriptomic analysis uncovers diverse and dynamic senescent cell populations.”

Senescence is a state of enduring growth arrest triggered by sublethal cell damage. Given that senescent cells actively secrete proinflammatory and matrix-remodeling proteins, their accumulation in tissues of older persons has been linked to many diseases of aging. Despite intense interest in identifying robust markers of senescence, the highly heterogeneous and dynamic nature of the senescent phenotype has made this task difficult.

In this new study, researchers Noah Wechter, Martina Rossi, Carlos Anerillas, Dimitrios Tsitsipatis, Yulan Piao, Jinshui Fan, Jennifer L. Martindale, Supriyo De, Krystyna Mazan-Mamczarz, and Myriam Gorospe from the National Institute on Aging set out to comprehensively analyze the senescent transcriptome of human diploid fibroblasts at the individual-cell scale by performing single-cell RNA-sequencing analysis through two approaches. 

“Here, we used single-cell RNA sequencing (scRNA-seq) analysis to document both the diverse transcriptomes of human senescent fibroblasts at an individual-cell scale, and the changes in the transcriptome over time during etoposide-triggered senescence.”

First, the researchers characterized the different cell states in cultures undergoing senescence triggered by different stresses, and found distinct cell subpopulations that expressed mRNAs encoding proteins with roles in growth arrest, survival and the secretory phenotype. Second, they characterized the dynamic changes in the transcriptomes of cells as they developed etoposide-induced senescence; by tracking cell transitions across this process, the researchers found two different senescence programs that developed divergently, one in which cells expressed traditional senescence markers such as p16 (CDKN2A) mRNA, and another in which cells expressed long noncoding RNAs and splicing was dysregulated. Finally, they obtained evidence that the proliferation status at the time of senescence initiation affected the path of senescence, as determined based on the expressed RNAs. 

“We propose that a deeper understanding of the transcriptomes during the progression of different senescent cell phenotypes will help develop more effective interventions directed at this detrimental cell population.”

DOI - https://doi.org/10.18632/aging.204666

Corresponding authors - Krystyna Mazan-Mamczarz - krystyna.mazan-mamczarz@nih.gov, and Myriam Gorospe - myriam-gorospe@nih.gov

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Keywords - aging, senescence, single-cell analysis, transcriptome

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Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Single-Cell Transcriptomic Analysis Uncovers Diverse and Dynamic Senescent Cell Populations

A new editorial paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 8, entitled, “The senescence-associated secretory phenotype induces neuroendocrine transdifferentiation.”

In this editorial, researchers Anda Huna, Nadine Martin and David Bernard from the Université de Lyon discuss the senescence-associated secretory phenotype (SASP). SASP, in addition to stable proliferation arrest, is one of the most remarkable characteristics of senescent cells. Indeed, these cells secrete a variety of factors including cytokines, growth factors and matrix metalloproteases among others. In response to stress, through their SASP, senescent cells are able to modify and instruct their microenvironment. 

“The SASP is known to have several, sometimes contradictory, effects on phenotypes, including the induction or reinforcement of senescence in neighboring cells, promotion or inhibition of stemness, modification of extracellular matrix, activation or inhibition of immune responses and induction of epithelial-mesenchymal transition and cell migration.” 

Although cellular senescence and its SASP can initially display some beneficial effects, for instance favoring wound healing or blocking tumor initiation, accumulation of senescent cells and their secretome during aging or chronic stresses (tobacco, obesity, alcohol among others) plays a significant role in promoting aging-associated features and pathologies, like fibrosis, steatosis, chronic inflammation or cancer. In the context of cancer, senescence initially has an antitumoral role, as it promotes proliferation arrest and favors an anti-tumoral immune surveillance in response to oncogenic stress or DNA damage accumulation. However, SASP plays a dual role in tumor initiation and progression, as it first has a tumor suppressive action by reinforcing senescence in neighboring cells and recruiting immune cells, but also plays a tumor promoting role by promoting stemness, epithelial-mesenchymal transition and cell migration and by inhibiting immune responses. 

“Overall our work reveals a new effect of senescent cells and their SASP in tumors and offers new insights into NED [neuroendocrine transdifferentiation] in breast and prostate cancer biology. It also provides a new vision of the contribution of senescent cells and their SASP to aging-related pathologies, which could involve NED induction in some contexts.”

DOI - https://doi.org/10.18632/aging.204669

Corresponding author - David Bernard - david.bernard@lyon.unicancer.fr

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Keywords - aging, cellular senescence, aging, cancer, NF-κB, calcium signaling

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Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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The Senescence-Associated Secretory Phenotype Induces Neuroendocrine Transdifferentiation

A new research paper was published on the cover of Aging (Aging-US) Volume 15, Issue 9, entitled, “In vitro and in vivo effects of zoledronic acid on senescence and senescence-associated secretory phenotype markers.”

Zoledronic acid has been found to reduce fracture risk and, in some studies, to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple comorbidities, the non-skeletal actions of zoledronic acid could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype (SASP)) actions.

In this new study, researchers Parinya Samakkarnthai, Dominik Saul, Lei Zhang, Zaira Aversa, Madison L. Doolittle, Jad G. Sfeir, Japneet Kaur, Elizabeth J. Atkinson, James R. Edwards, Graham G. Russell, Robert J. Pignolo, James L. Kirkland, Tamar Tchkonia, Laura J. Niedernhofer, David G. Monroe, Nathan K. Lebrasseur, Joshua N. Farr, Paul D. Robbins, and Sundeep Khosla from the Mayo Clinic, Phramongkutklao Hospital and College of Medicine, Eberhard Karls University, University of Minnesota, University of Oxford, and University of Sheffield tested the above hypothesis using multiple complementary approaches (in vitro, in vivo, and in silico) to evaluate possible effects of zoledronic acid on modulating cellular senescence.

The researchers first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronic acid killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronic acid or vehicle for 8 weeks, zoledronic acid significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ (CSF1R/c-fms+) pre-osteoclastic cells isolated from mice treated with zoledronic acid demonstrated a significant downregulation of senescence/SASP genes (SenMayo). 

To establish that these cells are potential senolytic/senomorphic targets of zoledronic acid, the team used single cell proteomic analysis (cytometry by time of flight [CyTOF]) and demonstrated that zoledronic acid significantly reduced the number of pre-osteoclastic (CD115+/CD3e-/Ly6G-/CD45R-) cells and decreased protein levels of p16, p21, and SASP markers in these cells without affecting other immune cell populations. 

“Collectively, our findings demonstrate that zoledronic acid has senolytic effects in vitro and modulates senescence/SASP biomarkers in vivo. These data point to the need for additional studies testing zoledronic acid and/or other bisphosphonate derivatives for senotherapeutic efficacy.”

DOI - https://doi.org/10.18632/aging.204701

Corresponding author - Sundeep Khosla - khosla.sundeep@mayo.edu

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Effects of Zoledronic Acid on Senescence and SASP Markers

A new research paper was published in Aging (Aging-US) Volume 15, Issue 10, entitled, “Key elements of cellular senescence involve transcriptional repression of mitotic and DNA repair genes through the p53-p16/RB-E2F-DREAM complex.”

Cellular senescence is a dynamic stress response process that contributes to aging. From initiation to maintenance, senescent cells continuously undergo complex molecular changes and develop an altered transcriptome. Understanding how the molecular architecture of these cells evolve to sustain their non-proliferative state will open new therapeutic avenues to alleviate or delay the consequences of aging. 

In this new study, seeking to understand these molecular changes, researchers Renuka Kandhaya-Pillai, Francesc Miro-Mur, Jaume Alijotas-Reig, Tamar Tchkonia, Simo Schwartz, James L. Kirkland, and Junko Oshima from the University of Washington, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital, and the Mayo Clinic studied the transcriptomic profiles of endothelial replication-induced senescence and senescence induced by the inflammatory cytokine, TNF-α. The researchers previously reported gene expressional pattern, pathways, and the mechanisms associated with upregulated genes during TNF-α induced senescence. 

“Here, we extend our work and find downregulated gene signatures of both replicative and TNF-α senescence were highly overlapped, involving the decreased expression of several genes associated with cell cycle regulation, DNA replication, recombination, repair, chromatin structure, cellular assembly, and organization.”

The team identified multiple targets of p53/p16-RB-E2F-DREAM that are essential for proliferation, mitotic progression, resolving DNA damage, maintaining chromatin integrity, and DNA synthesis that were repressed in senescent cells. They show that repression of multiple target genes in the p53/p16-RB-E2F-DREAM pathway collectively contributes to the stability of the senescent arrest. Their findings show that the regulatory connection between DREAM and cellular senescence may play a potential role in the aging process.

“This study suggests that the transcriptome signature of senescent cells goes beyond cell cycle arrest, with expression of multiple genes, from cell cycle to DNA repair to chromatin structure, being coordinately repressed to stably lock cells into this essentially non-proliferative state.”

DOI - https://doi.org/10.18632/aging.204743

Corresponding author - Renuka Kandhaya-Pillai - renugene@uw.edu

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Keywords - aging, cellular senescence, cell cycle, DREAM complex, DNA repair

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Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Cellular Senescence Involves Gene Repression Through p53-p16/RB-E2F-DREAM Complex

A new research paper was published in Aging (Aging-US) Volume 15, Issue 11, entitled, “Senescence and senotherapies in biliary atresia and biliary cirrhosis.”

Premature senescence occurs in adult hepatobiliary diseases and worsens the prognosis through deleterious liver remodeling and hepatic dysfunction. Senescence might also arise in biliary atresia (BA), the first cause of pediatric liver transplantation. Alternatives to transplantation are needed. In this new study, researchers Giulia Jannone, Eliano Bonaccorsi Riani, Catherine de Magnée, Roberto Tambucci, Jonathan Evraerts, Joachim Ravau, Pamela Baldin, Caroline Bouzin, Axelle Loriot, Laurent Gatto, Anabelle Decottignies, Mustapha Najimi, and Etienne Marc Sokal from the Université catholique de Louvain in Brussels, Belgium, aimed to investigate premature senescence in BA and to assess senotherapies in a preclinical model of biliary cirrhosis.

“As there is a need for new therapies to avoid or delay liver transplantation in pediatric biliary cirrhosis, the aim of our work was to investigate premature senescence in BA through a multi-technical approach and to assess senotherapies in a preclinical model of biliary cirrhosis.”

BA liver tissues were prospectively obtained at hepatoportoenterostomy (n=5) and liver transplantation (n=30) and compared to controls (n=10). Senescence was investigated through spatial whole transcriptome analysis, SA-β-gal activity, p16 and p21 expression, γ-H2AX and senescence-associated secretory phenotype (SASP). Human allogenic liver-derived progenitor cells (HALPC) or dasatinib and quercetin (D+Q) were administered to two-month-old Wistar rats after bile duct ligation (BDL).

Advanced premature senescence was evidenced in BA livers from early stage and continued to progress until liver transplantation. Senescence and SASP were predominant in cholangiocytes, but also present in surrounding hepatocytes. HALPC but not D+Q reduced the early marker of senescence p21 in BDL rats and improved biliary injury (serum γGT and Sox9 expression) and hepatocytes mass loss (Hnf4a). 

“BA livers displayed advanced cellular senescence at diagnosis that continued to progress until liver transplantation. HALPC reduced early senescence and improved liver disease in a preclinical model of BA, providing encouraging preliminary results regarding the use of senotherapies in pediatric biliary cirrhosis.”

DOI - https://doi.org/10.18632/aging.204700

Corresponding author - Giulia Jannone - giulia.jannone@uclouvain.be

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Keywords - aging, senescence, senotherapy, liver, biliary cirrhosis, biliary atresia

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Senescence and Senotherapies in Biliary Atresia and Biliary Cirrhosis

BUFFALO, NY- September 20, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 17, entitled, “Development of a DNA damage-induced senescence model in osteoarthritic chondrocytes.”

Senescent cells (SnCs) have been described to accumulate in osteoarthritis (OA) joint tissues in response to injury, thereby participating in OA development and progression. However, clinical therapeutic approaches targeting SnCs using senolysis, although promising in preclinical OA models, have not yet proven their efficacy in patients with knee OA. This pitfall may be due to the lack of understanding of the mechanisms underlying chondrocyte senescence. 

In their new study, researchers Mélina Georget, Anaïs Defois, Romain Guiho, Nina Bon, Sophie Allain, Cécile Boyer, Boris Halgand, Denis Waast, Gaël Grimandi, Alban Fouasson-Chailloux, Jérôme Guicheux, and Claire Vinatier from Nantes Université aimed to generate models of chondrocyte senescence.

“In this context, our study aims to develop in vitro models of chondrocyte senescence by investigating the ability of etoposide and IL-1β treatments to produce a reliable chondrocyte senescent model.”

This study used etoposide, to induce DNA damage-related senescence or chronic exposure to IL-1β to entail inflammation-related senescence in human OA chondrocytes. Several hallmarks of cellular senescence, such as cell cycle arrest, expression of cyclin-dependent kinase inhibitors, DNA damages, and senescence-associated secretory profile were evaluated. Chronic exposure to IL-1β induces only partial expression of senescence markers and does not allow us to conclude on its ability to induce senescence in chondrocytes. On the other hand, etoposide treatment reliably induces DNA damage-related senescence in human articular chondrocytes evidenced by loss of proliferative capacity, DNA damage accumulation, and expression of some SASP components.

“Etoposide-induced senescence model may help investigate the initiation of cellular senescence in chondrocytes, and provide a useful model to develop therapeutic approaches to target senescence in OA.”

DOI - https://doi.org/10.18632/aging.204881

Corresponding author - Claire Vinatier - claire.vinatier@univ-nantes.fr

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Keywords - aging, senescence, osteoarthritis, etoposide, chondrocytes

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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DNA Damage-induced Senescence Model in Osteoarthritic Chondrocytes

BUFFALO, NY- October 18, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 19, entitled, “Reduction of double-strand DNA break repair exacerbates vascular aging.”

Advanced age is the greatest risk factor for cardiovascular disease (CVD), the leading cause of death. Arterial function is impaired in advanced age which contributes to the development of CVD. One underexplored hypothesis is that DNA damage within arteries leads to this dysfunction, yet evidence demonstrating the incidence and physiological consequences of DNA damage in arteries, and in particular, in the microvasculature, in advanced age is limited.

In their new study, researchers Samuel I. Bloom, Jordan R. Tucker, Daniel R. Machin, Hossein Abdeahad, AdeLola O. Adeyemo, Tyler G. Thomas, R. Colton Bramwell, Lisa A. Lesniewski, and Anthony J. Donato from The University of Utah, Florida State University and the Veterans Affairs Medical Center-Salt Lake City began by assessing the abundance of DNA damage in human and mouse lung microvascular endothelial cells and found that aging increases the percentage of cells with DNA damage. 

“To explore the physiological consequences of increases in arterial DNA damage, we evaluated measures of endothelial function, microvascular and glycocalyx properties, and arterial stiffness in mice that were lacking or heterozygous for the double-strand DNA break repair protein ATM kinase.”

Surprisingly, in young mice, vascular function remained unchanged which led the researchers to rationalize that perhaps aging is required to accumulate DNA damage. Indeed, in comparison to wild type littermate controls, mice heterozygous for ATM that were aged to ~18 mo (Old ATM +/−) displayed an accelerated vascular aging phenotype characterized by increases in arterial DNA damage, senescence signaling, and impairments in endothelium-dependent dilation due to elevated oxidative stress. Furthermore, old ATM +/− mice had reduced microvascular density and glycocalyx thickness as well as increased arterial stiffness. 

“Collectively, these data demonstrate that DNA damage that accumulates in arteries in advanced age contributes to arterial dysfunction that is known to drive CVD.”

DOI - https://doi.org/10.18632/aging.205066

Corresponding author - Anthony J. Donato - tony.donato@utah.edu

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Keywords - aging, DNA damage, vascular function, endothelial cell, senescence, oxidative stress, arterial stiffness

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Reducing Double-strand DNA Break Repair Exacerbates Vascular Aging

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BUFFALO, NY- November 30, 2023 – A new #researchpaper was #published on the #cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 22, entitled, “Chronological aging impacts abundance, function and microRNA content of extracellular vesicles produced by human epidermal keratinocytes.”

The disturbance of intercellular communication is one of the hallmarks of aging. In their new study, researchers Taku Nedachi, Christelle Bonod, Julie Rorteau, Wafae Chinoune, Yuri Ishiuchi, Sandrine Hughes, Benjamin Gillet, Nicolas Bechetoille, Dominique Sigaudo-Roussel, and Jérôme Lamartine from the University of Lyon, Toyo University and Gattefossé SAS aimed to clarify the impact of chronological aging on extracellular vesicles (EVs), a key mode of communication in mammalian tissues. 

“The present study was therefore conducted to elucidate whether the characteristics of EVs released from cultured human keratinocytes can be modulated during aging process.”

The researchers focused on epidermal keratinocytes, the main cells of the outer protective layer of the skin which is strongly impaired in the skin of elderly. EVs were purified from conditioned medium of primary keratinocytes isolated from infant or aged adult skin. A significant increase of the relative number of EVs released from aged keratinocytes was observed whereas their size distribution was not modified.

By small RNA sequencing, the researchers described a specific microRNA (miRNA) signature of aged EVs with an increase abundance of miR-30a, a key regulator of barrier function in human epidermis. EVs from aged keratinocytes were found to be able to reduce the proliferation of young keratinocytes, to impact their organogenesis properties in a reconstructed epidermis model and to slow down the early steps of skin wound healing in mice, three features observed in aged epidermis. This work reveals that intercellular communication mediated by EVs is modulated during aging process in keratinocytes and might be involved in the functional defects observed in aged skin.

“To conclude, we have shown here that aging modulates EVs abundance, function and microRNA content in human keratinocytes.”
DOI - https://doi.org/10.18632/aging.205245

Corresponding author - Jérôme Lamartine - jerome.lamartine@univ-lyon1.fr

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Keywords - aging, keratinocytes, microRNA, senescence, exosomes

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Aging Modulates Extracellular Vesicles of Epidermal Keratinocytes

BUFFALO, NY- December 15, 2023 – A new #researchpaper was #published on the #cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 23, entitled, “Uncovering a unique pathogenic mechanism of SARS-CoV-2 omicron variant: selective induction of cellular senescence.”

SARS-CoV-2 variants are constantly emerging with a variety of changes in the conformation of the spike protein, resulting in alterations of virus entry mechanisms. Solely omicron variants use the endosomal clathrin-mediated entry. 

In this new study, researchers Franziska Hornung, Nilay Köse-Vogel, Claude Jourdan Le Saux, Antje Häder, Lea Herrmann, Luise Schulz, Lukáš Radosa, Thurid Lauf, Tim Sandhaus, Patrick Samson, Torsten Doenst, Daniel Wittschieber, Gita Mall, Bettina Löffler, and Stefanie Deinhardt-Emmer from Jena University, Leibniz Centre for Photonics in Infection Research (LPI), University of California San Francisco, Klinik für Herz- und Thoraxchirurgie, and University Hospital Bonn investigated the influence of defined altered spike formations to study their impact on premature cellular senescence.

“In our study, in vitro infections of SARS-CoV-2 variants delta (B.1.617.2) and omicron (B.1.1.529) were analyzed by using human primary small alveolar epithelial cells and human ex vivo lung slices. We confirmed cellular senescence in human lungs of COVID-19 patients. Hence, global gene expression patterns of infected human primary alveolar epithelial cells were identified via mRNA sequencing.”

Solely omicron variants of SARS-CoV-2 influenced the expression of cell cycle genes, highlighted by an increased p21 expression in human primary lung cells and human ex vivo lungs. Additionally, an upregulated senescence-associated secretory phenotype (SASP) was detected. Transcriptomic data indicate an increased gene expression of p16, and p38 in omicron-infected lung cells. Significant changes due to different SARS-CoV-2 infections in human primary alveolar epithelial cells with an overall impact on premature aging could be identified. A substantially different cellular response with an upregulation of cell cycle, inflammation- and integrin-associated pathways in omicron infected cells indicates premature cellular senescence.

“This difference may be attributed to the distinct endocytic cell entry and intracellular pathways of the omicron variant when compared to the delta variant. The induction of cellular senescence in lung tissue following acute SARS-CoV-2 infection could potentially contribute to the reported cytokine storm and the development of long-COVID.”

DOI - https://doi.org/10.18632/aging.205297

Corresponding author - Stefanie Deinhardt-Emmer - stefanie.deinhardt-emmer@med.uni-jena.de

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Keywords - aging, SARS-CoV-2, variant of concern, cellular senescence, lung airway cells

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Unique Pathogenic Mechanism of SARS-CoV-2 Omicron Variant: Induction of Cellular Senescence

BUFFALO, NY- December 20, 2023 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 23, entitled, “Benidipine calcium channel blocker promotes the death of cigarette smoke-induced senescent cells and improves lung emphysema.”

Smoking is the main risk factor for many lung diseases including chronic obstructive pulmonary disease. Cigarette smoke (CS) contains carcinogenic and reactive oxygen species that favor DNA mutations and perturb the homeostasis and environment of cells. CS induces lung cell senescence resulting in a stable proliferation arrest and a senescence-associated secretory phenotype. It was recently reported that senescent cell accumulation promotes several lung diseases. 

In this new study, researchers Alberta Palazzo, Gabriela Makulyte, Delphine Goerhig, Jean-Jacques Médard, Vincent Gros, François Trottein, Serge Adnot, David Vindrieux, Jean-Michel Flaman, and David Bernard from Université de Lyon, Equipe Labellisée la Ligue Contre le Cancer, Université Paris Est Créteil, Hôpital Henri Mondor, and Université Lille performed a chemical screen, using an FDA-approved drug library, to identify compounds selectively promoting the death of CS-induced senescent lung cells. 

“Here, our aim was to identify senolytic compounds in the context of CS-induced senescence and to assess whether they improved lung emphysema.”

Aside from the well-known senolytic, ABT-263, the researchers identified other potentially new senescence-eliminating compounds, including a new class of molecules, the dihydropyridine family of calcium voltage-gated channel (CaV) blockers. Among these blockers, Benidipine decreased senescent lung cells and ameliorates lung emphysema in a mouse model. The dihydropyridine family of CaV blockers thus constitutes a new class of senolytics that could improve lung diseases. 

“Hence, our work paves the way for further studies on the senolytic activity of CaV blockers in different senescence contexts and age-related diseases.”

DOI - https://doi.org/10.18632/aging.205259

Corresponding author - David Bernard - david.bernard@lyon.unicancer.fr

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Keywords - aging, senolytic, cigarette smoke, lung disease, cellular senescence, calcium channel

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Benidipine Calcium Channel Blocker Improves Cigarette Smoke-Induced Lung Emphysema

BUFFALO, NY- February 29, 2024 – A new #research paper was #published on the #cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 4, entitled, “Mapping the core senescence phenotype of primary human colon fibroblasts.”

Advanced age is the largest risk factor for many diseases and several types of cancer, including colorectal cancer (CRC). Senescent cells are known to accumulate with age in various tissues, where they can modulate the surrounding tissue microenvironment through their senescence associated secretory phenotype (SASP). Recently, researchers showed that there is an increased number of senescent cells in the colons of CRC patients and demonstrated that senescent fibroblasts and their SASP create microniches in the colon that are conducive to CRC onset and progression. However, the composition of the SASP is heterogenous and cell-specific, and the precise senescence profile of colon fibroblasts has not been well-defined. 

In this new study, to generate a SASP atlas of human colon fibroblasts, researchers Namita Ganesh Hattangady, Kelly Carter, Brett Maroni-Rana, Ting Wang, Jessica Lee Ayers, Ming Yu, and William M. Grady from Fred Hutchinson Cancer Center and the University of Washington School of Medicine induced senescence in primary human colon fibroblasts using various in vitro methods and assessed the resulting transcriptome. 

“[...] we utilized various relevant stressors to induce senescence in primary cultures of colon fibroblasts and perform RNA sequencing (RNASeq) to define an atlas of stressor-specific senescent profiles and a core senescent profile that is commonly regulated by all senescence inducers.”

Using RNA Sequencing and further validation by quantitative RT-PCR and Luminex assays, the team define and validate a ‘core senescent profile’ that might play a significant role in shaping the colon microenvironment. They also performed KEGG analysis and GO analyses to identify key pathways and biological processes that are differentially regulated in colon fibroblast senescence. These studies provide insights into potential driver proteins involved in senescence-associated diseases, like CRC, which may lead to therapies to improve overall health in the elderly and to prevent CRC.

“Further studies will be needed to address the limitations of our study and to translate our understanding of the SASP and disease into clinical care.”

DOI - https://doi.org/10.18632/aging.205577

Corresponding authors - William M. Grady - wgrady@fredhutch.org, and Ming Yu - myu@fredhutch.org

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Keywords - aging, senescence, senescence associated secretory phenotype, SASP, colorectal cancer, cancer

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Mapping the Core Senescence Phenotype of Human Colon Fibroblasts

BUFFALO, NY- March 19, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 5, entitled, “PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation.”

Cellular senescence is a permanent cell cycle arrest that can be triggered by both internal and external genotoxic stressors, such as telomere dysfunction and DNA damage. The execution of senescence is mainly by two pathways, p16/RB and p53/p21, which lead to CDK4/6 inhibition and RB activation to block cell cycle progression. While the regulation of p53/p21 signaling in response to DNA damage and other insults is well-defined, the regulation of the p16/RB pathway in response to various stressors remains poorly understood. 

In this new study, researchers Chitra Palanivel, Lepakshe S. V. Madduri, Ashley L. Hein, Christopher B. Jenkins, Brendan T. Graff, Alison L. Camero, Sumin Zhou, Charles A. Enke, Michel M. Ouellette, and Ying Yan from the University of Nebraska Medical Center report a novel function of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, as a potent inhibitor of p16 expression and senescence induction by ionizing radiation (IR), such as γ-rays. 

“During natural aging, there is a gradual accumulation of p16-expressing senescent cells in tissues [76]. To investigate the significance of PR55α in this up-regulation of p16, we compared levels of the p16 and PR55α proteins in a panel of normal tissue specimens derived from young (≤43 y/o) and old (≥68 y/o) donors.”

The results show that ectopic PR55α expression in normal pancreatic cells inhibits p16 transcription, increases RB phosphorylation, and blocks IR-induced senescence. Conversely, PR55α-knockdown by shRNA in pancreatic cancer cells elevates p16 transcription, reduces RB phosphorylation, and triggers senescence induction after IR. Furthermore, this PR55α function in the regulation of p16 and senescence is p53-independent because it was unaffected by the mutational status of p53. Moreover, PR55α only affects p16 expression but not p14 (ARF) expression, which is also transcribed from the same CDKN2A locus but from an alternative promoter. In normal human tissues, levels of p16 and PR55α proteins were inversely correlated and mutually exclusive. 

“Collectively, these results describe a novel function of PR55α/PP2A in blocking p16/RB signaling and IR-induced cellular senescence.”

DOI - https://doi.org/10.18632/aging.205619

Corresponding authors - Michel M. Ouellette - mouellet@unmc.edu, and Ying Yan - yyan@unmc.edu

About Aging-US:

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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PR55α-controlled PP2A Inhibits p16 Expression and Blocks Cellular Senescence Induction

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A traditional, twice-monthly, peer-reviewed, open-access journal covering all areas of research on aging and age-related diseases, including cancer and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome.

Read about the Aging (Aging-US) Scientific Integrity Process: https://aging-us.com/scientific-integrity

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