Aging-US

Dr. Masaya Koshizaka from the Department of Endocrinology, Hematology, and Gerontology at Chiba University Graduate School of Medicine, details a research paper he co-authored that was published by Aging (Aging-US) in Volume 15, Issue 9, entitled, “Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.” DOI - https://doi.org/10.18632/aging.204681 Corresponding authors - Masaya Koshizaka - overslope@chiba-u.jp, and Koutaro Yokote - kyokote@faculty.chiba-u.jp Transcription - https://aging-us.net/2023/06/09/behind-the-study-key-outcomes-observed-in-follow-up-study-using-the-werner-syndrome-registrybehind-the-study/ Video - https://www.youtube.com/watch?v=HFqPvtYYTGE Abstract Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204681 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, disease profile, long-term follow-up, malignant neoplasm, renal function, Werner syndrome 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

As we age, our immune system undergoes changes that influence our susceptibility to various diseases. Certain factors, such as smoking, viruses, age, and sex can have differential impacts on our various circulating immune cells. How changes to these immune cells contribute to cardiovascular disease and other age-related diseases is not yet fully understood. More research is needed to fully understand the underlying mechanisms and implications. “Understanding the composition of circulating immune cells with aging and the underlying biologic mechanisms driving aging may provide molecular targets to slow the aging process and reduce age-related disease.” In a new study, researchers Yuan Fang, Margaret F. Doyle, Jiachen Chen, Jesse Mez, Claudia L. Satizabal, Michael L. Alosco, Wei Qiao Qiu, Kathryn L. Lunetta, and Joanne M. Murabito from Boston University, Boston Medical Center, University of Vermont, and University of Texas Health Science Center aimed to characterize the circulating innate and adaptive immune system by profiling immune cell phenotypes from a community-based cohort. Their research paper was published in Aging’s Volume 15, Issue 10, on April 27, 2023, entitled, “Circulating immune cell phenotypes are associated with age, sex, CMV, and smoking status in the Framingham Heart Study offspring participants.” “We hypothesize that we will identify immune cell phenotype and ARIP [age-related immune phenotype] measure associations with CMV serostatus, age, and sex, as well as associations with cardiovascular risk factors.” Full blog - https://aging-us.org/2023/06/the-impact-of-age-sex-cmv-and-smoking-on-circulating-immune-cells/ Paper DOI - https://doi.org/10.18632/aging.204686 Corresponding author - Yuan Fang - yfang8@binghamton.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204686 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, immune cell, CMV, T cells, smoking 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

A new research paper was published in Aging (Aging-US) Volume 15, Issue 10, entitled, “DNAmFitAge: biological age indicator incorporating physical fitness.” Physical fitness is a well-known correlate of health and the aging process and DNA methylation (DNAm) data can capture aging via epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance fitness in their construction. In this new study, researchers develop blood-based DNAm biomarkers for fitness parameters including gait speed (walking speed), maximum handgrip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max) which have modest correlation with fitness parameters in five large-scale validation datasets (average r between 0.16–0.48). “These parameters were chosen because handgrip strength and VO2max provide insight into the two main categories of fitness: strength and endurance [23], and gait speed and FEV1 provide insight into fitness-related organ function: mobility and lung function [8, 24].” The researchers then used these DNAm fitness parameter biomarkers with DNAmGrimAge, a DNAm mortality risk estimate, to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness. DNAmFitAge was associated with low-intermediate physical activity levels across validation datasets (p = 6.4E-13), and younger/fitter DNAmFitAge corresponds to stronger DNAm fitness parameters in both males and females. DNAmFitAge was lower (p = 0.046) and DNAmVO2max is higher (p = 0.023) in male body builders compared to controls. Physically fit people had a younger DNAmFitAge and experienced better age-related outcomes: lower mortality risk (p = 7.2E-51), coronary heart disease risk (p = 2.6E-8), and increased disease-free status (p = 1.1E-7). These new DNAm biomarkers provide researchers a new method to incorporate physical fitness into epigenetic clocks. “Our newly constructed DNAm biomarkers and DNAmFitAge provide researchers and physicians a new method to incorporate physical fitness into epigenetic clocks and emphasizes the effect lifestyle has on the aging methylome.” DOI - https://doi.org/10.18632/aging.204538 Corresponding authors - Kristen M. McGreevy - kristenmae@ucla.edu, Zsolt Radak - radak.zsolt@tf.hu, and Steve Horvath - shorvath@mednet.ucla.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204538 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, epigenetics, physical fitness, biological age, DNA methylation 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

A new research paper was published in Aging (Aging-US) Volume 15, Issue 9, entitled, “Exogenous exposures shape genetic predisposition to lipids, Alzheimer’s, and coronary heart disease in the MLXIPL gene locus.” In this new study, researchers Yury Loika, Elena Loiko, Fan Feng, Eric Stallard, Anatoliy I. Yashin, Konstantin Arbeev, Allison L. Kuipers, Mary F. Feitosa, Michael A. Province, and Alexander M. Kulminski from Duke University, University of Pittsburgh and Washington University School of Medicine examined associations of single nucleotide polymorphisms (SNPs) of the MLXIPL lipid gene with Alzheimer’s (AD) and coronary heart disease (CHD) and potentially causal mediation effects of their risk factors, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in two samples of European ancestry from the United States (US) (22,712 individuals 587/2,608 AD/CHD cases) and the United Kingdom Biobank (UKB) (232,341 individuals; 809/15,269 AD/CHD cases). “Our results suggest that these associations can be regulated by several biological mechanisms and shaped by exogenous exposures.” Two patterns of associations (represented by rs17145750 and rs6967028) were identified. Minor alleles of rs17145750 and rs6967028 demonstrated primary (secondary) association with high TG (lower HDL-C) and high HDL-C (lower TG) levels, respectively. The primary association explained ~50% of the secondary one suggesting partly independent mechanisms of TG and HDL-C regulation. The magnitude of the association of rs17145750 with HDL-C was significantly higher in the US vs. UKB sample and likely related to differences in exogenous exposures in the two countries. rs17145750 demonstrated a significant detrimental indirect effect through TG on AD risk in the UKB only (βIE = 0.015, pIE = 1.9 × 10−3), which suggests protective effects of high TG levels against AD, likely shaped by exogenous exposures. Also, rs17145750 demonstrated significant protective indirect effects through TG and HDL-C in the associations with CHD in both samples. In contrast, rs6967028 demonstrated an adverse mediation effect through HDL-C on CHD risk in the US sample only (βIE = 0.019, pIE = 8.6 × 10−4). This trade-off suggests different roles of triglyceride mediated mechanisms in the pathogenesis of AD and CHD. “Finally, the results of this study suggest that genetic associations of SNPs from the MLXIPL gene locus with lipids, AD, and CHD are shaped by exogenous exposures. Further study of the related biological mechanisms can help to elucidate the related, modifiable risk factors.” DOI - https://doi.org/10.18632/aging.204665 Corresponding authors - Yury Loika - yury.loika@duke.edu, and Alexander M. Kulminski - alexander.kulminski@duke.edu Keywords - aging, MLXIPL, lipids, triglycerides, coronary heart disease, Alzheimer’s disease 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

A new research paper was published in Aging (Aging-US) Volume 15, Issue 9, entitled, “Highly multiplexed immune profiling throughout adulthood reveals kinetics of lymphocyte infiltration in the aging mouse prostate.” Aging is a significant risk factor for disease in several tissues, including the prostate. Defining the kinetics of age-related changes in these tissues is critical for identifying regulators of aging and evaluating interventions to slow the aging process and reduce disease risk. An altered immune microenvironment is characteristic of prostatic aging in mice, but whether features of aging in the prostate emerge predominantly in old age or earlier in adulthood has not previously been established. In this study, researchers Jonathan J. Fox, Takao Hashimoto, Héctor I. Navarro, Alejandro J. Garcia, Benjamin L. Shou, and Andrew S. Goldstein from the University of California Los Angeles tracked the abundance of 29 immune cell clusters in the aging mouse prostate using highly multiplexed immune profiling and time-course analysis. “In this study, we characterized how the inflammatory microenvironment of the adult mouse prostate changes during aging using highly-multiplexed single-cell mass cytometry.” Early in adulthood, myeloid cells comprise the vast majority of immune cells in the 3-month-old mouse prostate. Between 6 and 12 months of age, there is a profound shift towards a T and B lymphocyte-dominant mouse prostate immune microenvironment. Comparing the prostate to other urogenital tissues, the researchers found similar features of age-related inflammation in the mouse bladder but not the kidney. “In summary, our study offers new insight into the kinetics of prostatic inflammaging and the window when interventions to slow down age-related changes may be most effective.” DOI - https://doi.org/10.18632/aging.204708 Corresponding author - Andrew S. Goldstein - AGoldstein@mednet.ucla.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204708 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, prostate, immune microenvironment, mass cytometry, inflammation, lymphocyte 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Blog summary: "Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes." ______________________________________________ A healthy brain continuously produces new proteins to support synaptic plasticity, maintain neuronal health, facilitate signaling pathways, produce neurotransmitters, enable neuroplasticity and adaptation, and meet its metabolic demands. These processes are essential for normal brain function, learning, memory, and overall cognitive abilities. Researchers believe that the dysregulation of proteins is at the core of brain aging. However, the exact recipe for protein dysregulation that leads to accelerated brain aging and neurodegenerative disorders has yet to be brought to light. Previous brain proteostasis (referring to the maintenance of protein homeostasis in brain cells) studies in individuals with Alzheimer’s disease (AD) pathology and age-related neuropathological changes have shown protein dysregulation leading to a buildup of amyloid plaques and neurofibrillary tangles. While these studies have greatly enhanced our knowledge of brain aging, gaps in our understanding remain. What proteomic characteristics do healthy brain aging individuals—without neurodegenerative disorders—have in common? “To our knowledge, whole phosphoproteomes centered on the human brain aging without AD pathology are unavailable.” In a new study, researchers Pol Andrés-Benito, Ignacio Íñigo-Marco, Marta Brullas, Margarita Carmona, José Antonio del Rio, Joaquín Fernández-Irigoyen, Enrique Santamaría, Mónica Povedano, and Isidro Ferrer from Bellvitge Institute for Biomedical Research, Universidad Pública de Navarra, Barcelona Institute for Science and Technology, and University of Barcelona aimed to shed light on the mechanisms underlying brain aging in the absence of AD pathology and age-related neuropathological changes. Their research paper was published on May 13, 2023, in Aging’s Volume 15, Issue 9, and entitled, “Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes.” Full blog - https://aging-us.org/2023/05/brain-aging-insights-from-individuals-without-neurodegeneration/ Paper DOI - https://doi.org/10.18632/aging.204698 Corresponding authors - Isidro Ferrer - 8082ifa@gmail.com, and Pol Andrés-Benito - pandres@idibell.cat Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204698 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, brain aging, cytoskeleton, membranes, synapsis, mitochondria, kinases, (phospho)proteomics, proteome 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Impact Journals (Aging's publisher) will be participating as an exhibitor at the Society for Scholarly Publishing (SSP) 45th Annual Meeting, which convenes on May 31–June 2, 2023, at the Oregon Convention Center & Hyatt Regency Portland in Portland, Oregon, USA. This year, the SSP’s meeting theme is: “Transformation, Trust, and Transparency.” “The pace of change in our industry continues unabated, with seismic shifts in areas such as the dissemination of research, business models, and the nature of the workplace. And yet, while pressure for change has become the new normal, fundamental change has proved more elusive. We invite you to join us in highlighting the Trust and Transparency issues that underlie many of the challenges we face and exploring what it takes to create more meaningful Transformation in scholarly publishing.” (Source: sspnet.org) Visit booth No. 216 at the SSP 45th Annual Meeting to connect with members of the Impact Journals team. About Impact Journals: Impact Journals publishes scholarly journals in the biomedical sciences with a focus on all areas of cancer and aging research. Our mission is to provide scientists with the opportunity to share their exceptional discoveries, to offer services that enable rapid dissemination of results, and to present vital findings from the many fields of biomedical science. Our goal is life without disease. To learn more about Impact Journals, visit www.ImpactJournals.com. Connect with us on social media to stay updated on journals published by Impact Journals: Oncotarget Twitter – https://twitter.com/Oncotarget Aging Twitter – https://twitter.com/AgingJrnl Oncotarget Facebook – https://www.facebook.com/Oncotarget Aging Facebook – https://www.facebook.com/AgingUS Oncotarget YouTube – https://www.youtube.com/@OncotargetJournal Aging YouTube – https://www.youtube.com/@AgingJournal Oncotarget LinkedIn – https://www.linkedin.com/company/oncotarget/ Aging LinkedIn – https://www.linkedin.com/company/aging For media requests, please contact media@impactjournals.com.

Dean Bunnell, PhD candidate from the Department of Biological Sciences at the University of Alabama, describes a research paper he co-authored that was published by Aging (Aging-US) in Volume 15, Issue 6, entitled, “RNA virus-mediated changes in organismal oxygen consumption rate in young and old Drosophila melanogaster males.” DOI - https://doi.org/10.18632/aging.204593 Corresponding author - Stanislava Chtarbanova - schtarbanova@ua.edu Abstract Aging is accompanied by increased susceptibility to infections including with viral pathogens resulting in higher morbidity and mortality among the elderly. Significant changes in host metabolism can take place following virus infection. Efficient immune responses are energetically costly, and viruses divert host molecular resources to promote their own replication. Virus-induced metabolic reprogramming could impact infection outcomes, however, how this is affected by aging and impacts organismal survival remains poorly understood. RNA virus infection of Drosophila melanogaster with Flock House virus (FHV) is an effective model to study antiviral responses with age, where older flies die faster than younger flies due to impaired disease tolerance. Using this aged host-virus model, we conducted longitudinal, single-fly respirometry studies to determine if metabolism impacts infection outcomes. Analysis using linear mixed models on Oxygen Consumption Rate (OCR) following the first 72-hours post-infection showed that FHV modulates respiration, but age has no significant effect on OCR. However, the longitudinal assessment revealed that OCR in young flies progressively and significantly decreases, while OCR in aged flies remains constant throughout the three days of the experiment. Furthermore, we found that the OCR signature at 24-hours varied in response to both experimental treatment and survival status. FHV-injected flies that died prior to 48- or 72-hours measurements had a lower OCR compared to survivors at 48-hours. Our findings suggest the host’s metabolic profile could influence the outcome of viral infections. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204593 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, Drosophila melanogaster, virus infection, single-fly respirometry, metabolism 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

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 9, entitled, “Increased expression of musashi 1 on breast cancer cells has implication to understand dormancy and survival in bone marrow.” Breast cancer (BC) stem cells (CSCs) resist treatment and can exist as dormant cells in tissues such as the bone marrow (BM). Years before clinical diagnosis, BC cells (BCCs) could migrate from the primary site where the BM niche cells facilitate dedifferentiation into CSCs. Additionally, dedifferentiation could occur by cell autonomous methods. In this new study, researchers George R. Nahas, Lauren S. Sherman, Garima Sinha, Markos H. El Far, Andrew Petryna, Steven M. Munoz, Kimberly A. Silverio, Maran Shaker, Pujan Neopane, Veronica Mariotti, and Pranela Rameshwar from Rutgers New Jersey Medical School studied the role of the RNA-binding protein, Musashi I (Msi 1). They also analyzed its relationship with the T-cell inhibitory molecule programmed death-ligand 1 (PD-L1) in CSCs. “We validated the link between Msi 1 and PD-L1 in CSCs [cancer stem cells] based on significant reduction of CSCs following Msi 1 knockdown.” PD-L1 is expressed on triple negative BC and other cancers. Therefore, PD-L1 is an immune checkpoint that is a target in immune therapy for cancers. Msi 1 can support BCC growth through stabilization of oncogenic transcripts and modulation of stem cell-related gene expression. The researchers reported on a role for Msi 1 to maintain CSCs. They found that it seemed to occur by the differentiation of CSCs to more matured BCCs. This correlated with increased transition from cycling quiescence and reduced expression of stem cell-linked genes. CSCs co-expressed Msi 1 and PD-L1. Msi 1 knockdown led to a significant decrease in CSCs with undetectable PD-L1. “This study has implications for Msi 1 as a therapeutic target, in combination with [an] immune checkpoint inhibitor. Such treatment could also prevent dedifferentiation of breast cancer to CSCs, and to reverse tumor dormancy. The proposed combined treatment might be appropriate for other solid tumors.” DOI - https://doi.org/10.18632/aging.204620 Corresponding author - Pranela Rameshwar - rameshwa@njms.rutgers.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204620 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, cancer stem cell, breast cancer, musashi 1, bone marrow, dormancy 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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

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. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM