Neuroscience

Oncotarget

Intraventricular Immunovirotherapy; A Translational Step Forward | Oncotarget
Copy: Oncotarget published this trending research perspective in Volume 14, entitled, “Intraventricular immunovirotherapy; a translational step forward" by the researchers from the Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA; Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL.

DOI - https://doi.org/10.18632/oncotarget.28343

Correspondence to - Joshua D. Bernstock - jbernstock@bwh.harvard.edu, Gregory K. Friedman - gfriedman@uabmc.edu

Abstract

Oncolytic virotherapy with intratumoral engineered type-1 herpes simplex virus (HSV) has been proven safe with promising efficacy in recent clinical trials for treatment of both pediatric and adult high-grade glioma. However, this approach excludes patients with tumors in surgically inaccessible and/or eloquent brain regions. Current delivery methods are also unable to access/treat those patients with metastatic disease in the spinal cord and/or leptomeningeal disease. A recent preclinical study has paved the way for clinical translation of intraventricular administration of oHSV by identifying and mitigating the toxicity associated with this route for therapeutic benefit in murine models of disseminated medulloblastoma. This work may ultimately allow for targeting of intractable disease and provides a feasible option for the repetitive dosing of clinically relevant immunovirotherapy, G207.

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Keywords - oncolytic virotherapy, herpes simplex virus (HSV), G207, intraventricular therapy, leptomeningeal disease

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Intraventricular Immunovirotherapy; A Translational Step Forward

Aging (Aging-US)

Aging-US published this research paper in Volume 14, Issue 24, entitled, "12-year evolution of multimorbidity patterns among older adults based on Hidden Markov Models" by researchers from Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola de Vallès), Spain; Programa de Doctorat en Metodologia de la Recerca Biomèdica i Salut Pública, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden; Stockholm Gerontology Research Center, Stockholm, Sweden; Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Unidad Docente Multiprofesional de Atención Familiar y Comunitaria Norte, Gerencia Asistencial Atención Primaria, Madrid Health Service, Madrid, Spain; Signal Theory and Communications Department, Universitat Politecnica de Catalunya, Barcelona, Spain; Unitat de Suport a la Recerca Metropolitana Nord, Fundació Institut Universitaria per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Mataró, Barcelona, Spain.

DOI - https://doi.org/10.18632/aging.204395

Corresponding author - Albert Roso-Llorach - aroso@idiapjgol.org, Amaia Calderón-Larrañaga - amaia.calderon.larranaga@ki.se 

Abstract

Background: The evolution of multimorbidity patterns during aging is still an under-researched area. We lack evidence concerning the time spent by older adults within one same multimorbidity pattern, and their transitional probability across different patterns when further chronic diseases arise. The aim of this study is to fill this gap by exploring multimorbidity patterns across decades of age in older adults, and longitudinal dynamics among these patterns.
Methods: Longitudinal study based on the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) on adults ≥60 years (N=3,363). Hidden Markov Models were applied to model the temporal evolution of both multimorbidity patterns and individuals' transitions over a 12-year follow-up.

Findings: Within the study population (mean age 76.1 years, 66.6% female), 87.2% had ≥2 chronic conditions at baseline. Four longitudinal multimorbidity patterns were identified for each decade. Individuals in all decades showed the shortest permanence time in an Unspecific pattern lacking any overrepresented diseases (range: 4.6-10.9 years), but the pattern with the longest permanence time varied by age. Sexagenarians remained longest in the Psychiatric-endocrine and sensorial pattern (15.4 years); septuagenarians in the Neuro-vascular and skin-sensorial pattern (11.0 years); and octogenarians and beyond in the Neuro-sensorial pattern (8.9 years). Transition probabilities varied across decades, sexagenarians showing the highest levels of stability.

Interpretation: Our findings highlight the dynamism and heterogeneity underlying multimorbidity by quantifying the varying permanence times and transition probabilities across patterns in different decades. With increasing age, older adults experience decreasing stability and progressively shorter permanence time within one same multimorbidity pattern.

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Keywords - multimorbidity, older adults, longitudinal population-based study, aging, Hidden Markov Models

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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12-year Evolution of Multimorbidity Patterns Among Older Adults Based on Hidden Markov Models

Aging-US published this trending research paper in Volume 14, Issue 24, entitled, "Epigenetic aging is associated with aberrant neural oscillatory dynamics serving visuospatial processing in people with HIV" by researchers from Institute for Human Neuroscience, Boys Town National Research Hospital, Boys Town, NE; College of Medicine, University of Nebraska Medical Center (UNMC), Omaha, NE; Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE; Institute of Clinical Neuroscience and Medical Psychology, Heinrich-Heine University, Düsseldorf, Germany, Department of Neurological Sciences, UNMC, Omaha, NE; Department of In ternal Medicine, Division of Infectious Diseases, UNMC, Omaha, NE; Department of Medicine, University of California San Diego, La Jolla, CA.

DOI - https://doi.org/10.18632/aging.204437

Corresponding author - Tony W. Wilson - tony.wilson@boystown.org 

Abstract

Background: Despite effective antiretroviral therapy, cognitive impairment and other aging-related comorbidities are more prevalent in people with HIV (PWH) than in the general population. Previous research examining DNA methylation has shown PWH exhibit accelerated biological aging. However, it is unclear how accelerated biological aging may affect neural oscillatory activity in virally suppressed PWH, and more broadly how such aberrant neural activity may impact neuropsychological performance.

Methods: In the present study, participants (n = 134) between the ages of 23 – 72 years underwent a neuropsychological assessment, a blood draw to determine biological age via DNA methylation, and a visuospatial processing task during magnetoencephalography (MEG). Our analyses focused on the relationship between biological age and oscillatory theta (4-8 Hz) and alpha (10 - 16 Hz) activity among PWH (n=65) and seronegative controls (n = 69).

Results: PWH had significantly elevated biological age when controlling for chronological age relative to controls. Biological age was differentially associated with theta oscillations in the left posterior cingulate cortex (PCC) and with alpha oscillations in the right medial prefrontal cortex (mPFC) among PWH and seronegative controls. Stronger alpha oscillations in the mPFC were associated with lower CD4 nadir and lower current CD4 counts, suggesting such responses were compensatory. Participants who were on combination antiretroviral therapy for longer had weaker theta oscillations in the PCC.

Conclusions: These findings support the concept of interactions between biological aging and HIV status on the neural oscillatory dynamics serving visuospatial processing. Future work should elucidate the long-term trajectory and impact of accelerated aging on neural oscillatory dynamics in PWH.

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Keywords - HIV, epigenetics, biological age, visuospatial discrimination, oscillations

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:

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Epigenetic Aging, Cognitive Function and Visuospatial Processing in People With HIV

Aging-US published this research paper as the cover for Volume 14, Issue 24, entitled, "Associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer’s disease biomarkers" by researchers from Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC; Center for Imaging of Neurodegenerative Disease, University of California, San Francisco, CA.

DOI - https://doi.org/10.18632/aging.204384 

Corresponding author - Alexander M. Kulminski - kulminsk@duke.edu 

Abstract

Capturing the genetic architecture of Alzheimer’s disease (AD) is challenging because of the complex interplay of genetic and non-genetic factors in its etiology. It has been suggested that AD biomarkers may improve the characterization of AD pathology and its genetic architecture. Most studies have focused on connections of individual genetic variants with AD biomarkers, whereas the role of combinations of genetic variants is substantially underexplored. We examined the associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with cerebrospinal fluid (CSF) and plasma amyloid β (Aβ40 and Aβ42) and tau biomarkers. Our findings support associations of the ε4 alleles with both plasma and CSF Aβ42 and CSF tau, and the ε2 alleles with baseline, but not longitudinal, CSF Aβ42 measurements. We found that the ε4-bearing polygenic profiles conferring higher and lower AD risks are differentially associated with tau but not Aβ42. Modulation of the effect of the ε4 alleles by TOMM40 and APOC1 variants indicates the potential genetic mechanism of differential roles of Aβ and tau in AD pathogenesis.
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Keywords - aging, apolipoprotein E polymorphism, Alzheimer’s disease, haplotypes, Alzheimer’s disease biomarkers

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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 Associations of APOE-TOMM40-APOC1 Variants With Alzheimer’s Disease Biomarkers

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Aging-US published this trending research paper in Volume 14, Issue 23, entitled, "White matter hyperintensity load is associated with premature brain aging" by researchers from Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC; Department of Psychology, University of South Carolina, Columbia, SC; Department of Health and Rehabilitation Sciences, Medical University of South Carolina, Charleston, SC; Department of Neurology, Emory University, Atlanta, GA.

DOI - https://doi.org/10.18632/aging.204397

Corresponding author - Natalie Busby - hethern@mailbox.sc.edu 

Abstract

Background: Brain age is an MRI-derived estimate of brain tissue loss that has a similar pattern to aging-related atrophy. White matter hyperintensities (WMHs) are neuroimaging markers of small vessel disease and may represent subtle signs of brain compromise. We tested the hypothesis that WMHs are independently associated with premature brain age in an original aging cohort.

Methods: Brain age was calculated using machine-learning on whole-brain tissue estimates from T1-weighted images using the BrainAgeR analysis pipeline in 166 healthy adult participants. WMHs were manually delineated on FLAIR images. WMH load was defined as the cumulative volume of WMHs. A positive difference between estimated brain age and chronological age (BrainGAP) was used as a measure of premature brain aging. Then, partial Pearson correlations between BrainGAP and volume of WMHs were calculated (accounting for chronological age).

Results: Brain and chronological age were strongly correlated (r(163)=0.932, p<0.001). There was significant negative correlation between BrainGAP scores and chronological age (r(163)=-0.244, p<0.001) indicating that younger participants had higher BrainGAP (premature brain aging). Chronological age also showed a positive correlation with WMH load (r(163)=0.506, p<0.001) indicating older participants had increased WMH load. Controlling for chronological age, there was a statistically significant relationship between premature brain aging and WMHs load (r(163)=0.216, p=0.003). Each additional year in brain age beyond chronological age corresponded to an additional 1.1mm3 in WMH load.

Conclusions: WMHs are an independent factor associated with premature brain aging. This finding underscores the impact of white matter disease on global brain integrity and progressive age-like brain atrophy.

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Keywords - brain age, white matter hyperintensity, brain health, aging, health

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:

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White Matter Hyperintensity Load Associated With Premature Brain Aging

Aging-US published this trending research paper in Volume 14, Issue 22, entitled, "Denervation induces mitochondrial decline and exacerbates lysosome dysfunction in middle-aged mice" by researchers from Muscle Health Research Centre, York University, Toronto, Ontario M3J 1P3, Canada; School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada. 

DOI - https://doi.org/10.18632/aging.204365

Corresponding author - David A. Hood - dhood@yorku.ca 

Abstract

With age, skeletal muscle undergoes a progressive decline in size and quality. Imbalanced mitochondrial turnover and the resultant dysfunction contribute to these phenotypic alterations. Motor neuron denervation (Den) is a contributor to the etiology of muscle atrophy associated with age. Further, aged muscle exhibits reduced plasticity to both enhanced and suppressed contractile activity. It remains unclear when the onset of this blunted response occurs, and how middle-aged muscle adapts to denervation. The purpose of this study was to compare mitochondrial turnover pathways in young (Y, ~5months) and middle-aged (MA, ~15months) mice, and determine the influence of Den. Transgenic mt-Keima mice were subjected to 1,3 or 7 days of Den. Muscle mass, mitochondrial content, and PGC-1α protein were not different between Y and MA mice. However, indications of enhanced mitochondrial fission and mitophagy were evident in MA muscle which were supported by a greater abundance of lysosome proteins. Den resulted in muscle atrophy and reductions in mitochondrial protein content by 7-days. These changes occurred concomitant with modest decreases in PGC-1α protein, but without further elevations in mitophagy. Although both autophagosomal and lysosomal proteins were elevated, evidence of lysosome dysfunction was present following Den in MA mice. These data suggest that increases in fission drive an acceleration of mitophagy in muscle of MA mice to preserve mitochondrial quality. Den exacerbates the aging phenotype by reducing biogenesis in the absence of a change in mitophagy, perhaps limited by lysosomal capacity, leading to an accumulation of dysfunctional mitochondria with an age-related loss of neuromuscular innervation.

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Keywords - mitochondrial biogenesis, autophagy, mitophagy, lysosomes, muscle

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:

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Denervation Induces Mitochondrial Decline and Lysosome Dysfunction in Middle-Aged Mice

Aging-US published this research paper in Volume 14, Issue 22, entitled, "The potential benefit of metformin to reduce delirium risk and mortality: a retrospective cohort study" by researchers from Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, Palo Alto, CA; University of Iowa Carver College of Medicine, Department of Psychiatry, Iowa City, IA; Tottori University Faculty of Medicine, Department of Neuropsychiatry, Yonago-Shi, Tottori, Japan; University of Iowa Carver College of Medicine, Department of Emergency Medicine, Iowa City, IA; University of Iowa College of Public Health, Department of Biostatistics, Iowa City, IA; University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, IA.
#openaccess   #aging   #metformin   #mortality    #researchpaper   #peerreview   #openscience #delirium #diabetes   

DOI - https://doi.org/10.18632/aging.204393

Corresponding author - Gen Shinozaki - gens@stanford.edu 

Abstract

Purpose: Metformin has been reported to improve age-related disorders, including dementia, and to lower mortality. This study was conducted to investigate whether metformin use lower delirium risk, as well as long-term mortality.

Methods: In this retrospective cohort study, previously recruited 1,404 subjects were analyzed. The relationship between metformin use and delirium, and the relationship between metformin use and 3-year mortality were investigated.

Main findings: 242 subjects were categorized into a type 2 diabetes mellitus (DM)-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for confounding factors. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for confounding factors (HR, 0.69 [95% CI, 0.48 to 0.98]).

Conclusions: Metformin use may lower the risk of delirium and mortality in DM patients.

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Keywords - delirium, metformin, diabetes mellitus, mortality, aging

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:

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Facebook - https://www.facebook.com/AgingUS/
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The Potential Benefit of Metformin to Reduce Delirium Risk and Mortality

Aging (Aging-US) published this trending research paper in Volume 14, Issue 21, entitled, “Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging” by researchers from the Institute of Clinical Medicine, Department of Clinical Molecular Biology, University of Oslo, Oslo N-0318, Norway; Section of Clinical Molecular Biology, Akershus University Hospital, Nordbyhagen N-1474, Norway; Department of Microbiology, Oslo University Hospital, Oslo N-0424, Norway; Department of Biosciences, University of Oslo, Oslo N-0318, Norway.

DOI - https://doi.org/10.18632/aging.204375

Corresponding author - Hilde Nilsen - hilde.nilsen@medisin.uio.no 

ABSTRACT

There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in long-chain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.

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Keywords - krill oil, aging, healthspan, mitochondrial health, senescence

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 http://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/agingus​
LinkedIn - https://www.linkedin.com/company/aging/
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Aging-US is published by Impact Journals, LLC: http://www.ImpactJournals.com​​

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