bims-senagi Biomed News
on Senescence and aging
Issue of 2022–08–21
thirty-six papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. A protocol for rapid construction of senescent cells.
  2. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues.
  3. Diagnostic and Therapeutic Roles of Extracellular Vesicles in Aging-Related Diseases.
  4. Senescent cells: A therapeutic target for osteoporosis.
  5. Senescence recovering by dual drug-encapsulated liposomal nanoparticles for large-scale human cell expansion.
  6. Cellular senescence in neuroinflammatory disease: new therapies for old cells?
  7. Immunosenescence, aging and successful aging.
  8. Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting.
  9. Role of cellular senescence in the pathogenesis of systemic sclerosis.
  10. Inflammatory and immune markers in HIV-infected older adults on long-term antiretroviral therapy: Persistent elevation of sCD14 and of proinflammatory effector memory T cells.
  11. Immunoglobulin G glycans - Biomarkers and molecular effectors of aging.
  12. Breaking the aging epigenetic barrier.
  13. Metabolic changes in aging humans: current evidence and therapeutic strategies.
  14. Molecular and histological correlates of cognitive decline across age in male C57BL/6J mice.
  15. Rapamycin/metformin co-treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice.
  16. Transcriptional Heterogeneity of Cellular Senescence in Cancer.
  17. Artificially stimulating retrotransposon activity increases mortality and accelerates a subset of aging phenotypes in Drosophila.
  18. B cell-intrinsic changes with age do not impact antibody-secreting cell formation but delay B cell participation in the germinal centre reaction.
  19. Reduced bone morphogenic protein signaling along the gut-neuron axis by heat shock factor promotes longevity.
  20. Inflammaging: The ground for sarcopenia?
  21. T cell senescence by N-glycan branching.
  22. Interplay of cGAS with micronuclei: regulation and diseases.
  23. Thermogenic adipose tissue aging: Mechanisms and implications.
  24. Therapeutic Targeting of Histone Deacetylation to Prevent Alzheimer's Disease.
  25. Herpes Simplex Virus Type 1 Preferentially Enhances Neuro-Inflammation and Senescence in Brainstem of Female Mice.
  26. BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
  27. Epigenetics, DNA damage, and aging.
  28. Characteristic Hallmarks of Aging and the Impact on Carcinogenesis.
  29. Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.
  30. The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging.
  31. CXCR6-based immunotherapy in autoimmune, cancer and inflammatory infliction.
  32. Nitric oxide-soluble guanylyl cyclase pathway as a contributor to age-related memory impairment in Drosophila.
  33. Glycation-induced age-related illnesses, antiglycation and drug delivery strategies.
  34. Ginsenoside Rg1 ameliorates apoptosis, senescence and oxidative stress in ox-LDL-induced vascular endothelial cells via the AMPK/SIRT3/p53 signaling pathway.
  35. Nicotinamide adenine dinucleotide attenuates acetaminophen-induced acute liver injury via activation of PARP1, Sirt1, and Nrf2 in mice.
  36. Adaptive cellular response of the substantia nigra dopaminergic neurons upon age-dependent iron accumulation.
  1. Front Integr Neurosci. 2022 ;16 929788
    A protocol for rapid construction of senescent cells.
    Xing Yu, Jing Quan, Shuai Chen, Xinyue Yang, Shuai Huang, Gang Yang, Yujing Zhang.
      Aging may be the largest factor for a variety of chronic diseases that influence survival, independence, and wellbeing. Evidence suggests that aging could be thought of as the modifiable risk factor to delay or alleviate age-related conditions as a group by regulating essential aging mechanisms. One such mechanism is cellular senescence, which is a special form of most cells that are present as permanent cell cycle arrest, apoptosis resistance, expression of anti-proliferative molecules, acquisition of pro-inflammatory, senescence-associated secretory phenotype (SASP), and others. Most cells cultured in vitro or in vivo may undergo cellular senescence after accruing a set number of cell divisions or provoked by excessive endogenous and exogenous stress or damage. Senescent cells occur throughout life and play a vital role in various physiological and pathological processes such as embryogenesis, wound healing, host immunity, and tumor suppression. In contrast to the beneficial senescent processes, the accumulation of senescent also has deleterious effects. These non-proliferating cells lead to the decrease of regenerative potential or functions of tissues, inflammation, and other aging-associated diseases because of the change of tissue microenvironment with the acquisition of SASP. While it is understood that age-related diseases occur at the cellular level from the cellular senescence, the mechanisms of cellular senescence in age-related disease progression remain largely unknown. Simplified and rapid models such as in vitro models of the cellular senescence are critically needed to deconvolute mechanisms of age-related diseases. Here, we obtained replicative senescent L02 hepatocytes by culturing the cells for 20 weeks. Then, the conditioned medium containing supernatant from replicative senescent L02 hepatocytes was used to induce cellular senescence, which could rapidly induce hepatocytes into senescence. In addition, different methods were used to validate senescence, including senescence-associated β-galactosidase (SA-β-gal), the rate of DNA synthesis using 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and senescence-related proteins. At last, we provide example results and discuss further applications of the protocol.
    Keywords:  SASP; aging; biomarker; cellular senescence; senescent cell models
    DOI:  https://doi.org/10.3389/fnint.2022.929788
  2. Nat Commun. 2022 Aug 16. 13(1): 4827
    A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues.
    Dominik Saul, Robyn Laura Kosinsky, Elizabeth J Atkinson, Madison L Doolittle, Xu Zhang, Nathan K LeBrasseur, Robert J Pignolo, Paul D Robbins, Laura J Niedernhofer, Yuji Ikeno, Diana Jurk, João F Passos, LaTonya J Hickson, Ailing Xue, David G Monroe, Tamara Tchkonia, James L Kirkland, Joshua N Farr, Sundeep Khosla.
      Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.
    DOI:  https://doi.org/10.1038/s41467-022-32552-1
  3. Oxid Med Cell Longev. 2022 ;2022 6742792
    Diagnostic and Therapeutic Roles of Extracellular Vesicles in Aging-Related Diseases.
    Zixuan Sun, Xiaomei Hou, Jiaxin Zhang, Jiali Li, Peipei Wu, Lirong Yan, Hui Qian.
      Aging shows a decline in overall physical function, and cellular senescence is the powerful catalyst leading to aging. Considering that aging will be accompanied with the emergence of various aging-related diseases, research on new antiaging drugs is still valuable. Extracellular vesicles (EVs), as tools for intercellular communication, are important components of the senescence-associated secretory phenotype (SASP), and they can play pathological roles in the process of cellular senescence. In addition, EVs are similar to their original cells in functions. Therefore, EVs derived from pathological tissues or body fluids may be closely related to the progression of diseases and become potential biomarkers, while those from healthy cells may have therapeutic effects. Moreover, EVs are satisfactory drug carriers. At present, numerous studies have supported the idea that engineered EVs could improve drug targeting ability and utilization efficiency. Here, we summarize the characteristics of EVs and cellular senescence and focus on the diagnostic and therapeutic potential of EVs in various aging-related diseases, including Alzheimer disease, osteoporosis, cardiovascular disease, diabetes mellitus and its complications, and skin aging.
    DOI:  https://doi.org/10.1155/2022/6742792
  4. Cell Prolif. 2022 Aug 19. e13323
    Senescent cells: A therapeutic target for osteoporosis.
    Tiantian Wang, Shishu Huang, Chengqi He.
       BACKGROUND: Osteoporosis (OP) is a prevalent disorder characterized by the loss of bone mass and the deterioration of bone microarchitecture. OP is attributed to various factors, including menopause (primary), ageing (primary) and the adverse effects of medications (secondary). Recently, cellular senescence has been shown to have a crucial role in the maintenance of cellular homeostasis and organ function. The purpose of this review is to summarize recent findings regarding the roles of bone cellular senescence and senescence-associated secretory phenotype (SASP) in OP.
    METHODS: A comprehensive search of the PubMed database from inception to July 2022 was performed regarding the molecular mechanism of bone cell senescence in OP progression.
    RESULTS: We describe the pathophysiology of senescent bone cells and SASP, and how each contributes to OP. We also provide new options for treating OP by targeting cellular senescence pathways.
    CONCLUSION: Cellular senescence plays an important role in bone homeostasis, with variations based on the different types of OP. These variations are associated with pathogenic factors, bone turnover rate and systemic metabolism. Understanding the molecular relationship between bone cells and senescence provides for the possible targeting of senescence as a means by which to treat OP.
    DOI:  https://doi.org/10.1111/cpr.13323
  5. J Artif Organs. 2022 Aug 19.
    Senescence recovering by dual drug-encapsulated liposomal nanoparticles for large-scale human cell expansion.
    Keisuke Ashiba, Koki Mino, Yui Okido, Kiyoshi Sato, Hiroyoshi Kawakami.
      Although regenerative therapy and bioartificial tissues and organs require a sufficient number of human cells, current cell expansion processes are accompanied by accumulation of senescent cells that are related to deterioration of cellular functions and induction of senescence-associated secretory phenotype (SASP). Therefore, suppression of replicative senescence during expansion is one of the crucial issues for dissemination of regenerative medicine. We herein developed dual drug-encapsulated liposomal nanoparticles (LNPs) to suppress cellular senescence in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) and natural killer (NK) cells by removal of dysfunctional mitochondria from the senescent cells. We found that LNP treatment reduced senescent makers; downregulation of p21 expression and reduction of SA-β-Gal activity in both cells provably due to mitophagy reactivation in the cells. Moreover, SASP secretion in hAT-MSCs and tumor cytotoxicity in NK cells were also improved upon LNP treatments. These findings may contribute to the production of highly effective expanded cells for regenerative medicine and bioartificial tissues and organs.
    Keywords:  Cellular senescence; Human cell expansion; Liposomal nanoparticles; Mesenchymal stem cells; Natural killer cells
    DOI:  https://doi.org/10.1007/s10047-022-01356-x
  6. Trends Mol Med. 2022 Aug 12. pii: S1471-4914(22)00183-6. [Epub ahead of print]
    Cellular senescence in neuroinflammatory disease: new therapies for old cells?
    Christopher Nelke, Christina B Schroeter, Marc Pawlitzki, Sven G Meuth, Tobias Ruck.
      Neuroinflammatory diseases remain a therapeutic challenge, notably when progressing towards neurodegeneration. In this context, multiple sclerosis represents a central nervous system (CNS) disorder that combines pathogenic inflammatory and degenerative processes. Immunosuppression is effective for managing inflammatory activity, but neurodegenerative processes secondary to chronic inflammation are often refractory to contemporary treatments. Recent evidence indicates that pathways involved in chronic neuroinflammation demonstrate features of cellular senescence. These features could provide a framework that could serve as a target for senotherapeutics. In this review, we discuss the unmet need for strategies capable of overcoming the treatment resistance of neuroinflammatory diseases, and we discuss the potential of cellular senescence towards developing these strategies.
    Keywords:  cellular senescence; neuroinflammation; senescence; senescence-associated secretory phenotype; senolytics; senotherapeutic
    DOI:  https://doi.org/10.1016/j.molmed.2022.07.003
  7. Front Immunol. 2022 ;13 942796
    Immunosenescence, aging and successful aging.
    Yunan Wang, Chen Dong, Yudian Han, Zhifeng Gu, Chi Sun.
      Aging induces a series of immune related changes, which is called immunosenescence, playing important roles in many age-related diseases, especially neurodegenerative diseases, tumors, cardiovascular diseases, autoimmune diseases and coronavirus disease 2019(COVID-19). However, the mechanism of immunosenescence, the association with aging and successful aging, and the effects on diseases are not revealed obviously. In order to provide theoretical basis for preventing or controlling diseases effectively and achieve successful aging, we conducted the review and found that changes of aging-related phenotypes, deterioration of immune organ function and alterations of immune cell subsets participated in the process of immunosenescence, which had great effects on the occurrence and development of age-related diseases.
    Keywords:  age-related diseases; centenarian; immunosenescence; inflammation; successful aging
    DOI:  https://doi.org/10.3389/fimmu.2022.942796
  8. Cell Mol Biol Lett. 2022 Aug 19. 27(1): 69
    Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting.
    Mahmoud Al-Azab, Mohammed Safi, Elina Idiiatullina, Fadhl Al-Shaebi, Mohamed Y Zaky.
      Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main  contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.
    Keywords:  Aging; Cellular senescence; Differentiation; Mesenchymal stem cell; Senescence markers; Anti-cellular senescence 
    DOI:  https://doi.org/10.1186/s11658-022-00366-0
  9. Curr Opin Rheumatol. 2022 Aug 17.
    Role of cellular senescence in the pathogenesis of systemic sclerosis.
    Pei-Suen Tsou, Bo Shi, John Varga.
       PURPOSE OF REVIEW: Systemic sclerosis (SSc) is a chronic rheumatic disease that is characterized by immune activation, vasculopathy and fibrosis of the skin and internal organs. It has been proposed that premature onset of ageing pathways and associated senescent changes in cells contribute to the clinical and pathological features of SSc. The aim of this review is to critically review recent insights into the involvement of cellular senescence in SSc.
    RECENT FINDINGS: Cellular senescence plays a critical role in SSc pathogenesis, particularly involving endothelial cells and fibroblasts. Immunosenescence could also contribute to SSc pathogenesis by direct alteration of cellular functions or indirect promotion of defective immune surveillance. Molecular studies have shed some light on how cellular senescence contributes to fibrosis. Recent and planned proof-of-concept trials using senotherapeutics showed promising results in fibrotic diseases, including SSc.
    SUMMARY: There is increasing evidence implicating cellular senescence in SSc. The mechanisms underlying premature cellular senescence in SSc, and its potential role in pathogenesis, merit further investigation. Emerging drugs targeting senescence-related pathways might be potential therapeutic options for SSc.
    DOI:  https://doi.org/10.1097/BOR.0000000000000898
  10. Aging Cell. 2022 Aug 16. e13681
    Inflammatory and immune markers in HIV-infected older adults on long-term antiretroviral therapy: Persistent elevation of sCD14 and of proinflammatory effector memory T cells.
    Makiko Watanabe, Mladen Jergovic, Lisa Davidson, Bonnie J LaFleur, Yvonne Castaneda, Carmine Martinez, Megan J Smithey, Raymond P Stowe, Elias K Haddad, Janko Nikolich-Žugich.
      HIV-positive patients whose viral loads are successfully controlled by active antiretroviral therapy (ART) show no clinical signs of AIDS. However, their lifespan is shorter compared with individuals with no HIV infection and they prematurely exhibit a multitude of chronic diseases typically associated with advanced age. It was hypothesized that immune system aging may correlate with, and provide useful biomarkers for, this premature loss of healthspan in HIV-positive subjects. Here, we tested whether the immune correlates of aging, including cell numbers and phenotypes, inflammatory status, and control of human cytomegalovirus (hCMV) in HIV-positive subjects on long-term successful ART (HIV+) may reveal increased "immunological age" compared with HIV-negative, age-matched cohort (HIV-) in participants between 50 and 69 years of age. Specifically, we expected that younger HIV+ subjects may immunologically resemble older individuals without HIV. We found no evidence to support this hypothesis. While T cells from HIV+ participants displayed differential expression in several differentiation and/or inhibitory/exhaustion markers in different T cell subpopulations, aging by a decade did not pronounce these changes. Similarly, while the HIV+ participants exhibited higher T cell responses and elevated inflammatory marker levels in plasma, indicative of chronic inflammation, this trait was not age-sensitive. We did find differences in immune control of hCMV, and, more importantly, a sustained elevation of sCD14 and of proinflammatory CD4 and CD8 T cell responses across age groups, pointing towards uncontrolled inflammation as a factor in reduced healthspan in successfully treated older HIV+ patients.
    Keywords:  HIV; antiretroviral therapy; immune aging; sCD14
    DOI:  https://doi.org/10.1111/acel.13681
  11. Clin Chim Acta. 2022 Aug 12. pii: S0009-8981(22)01257-8. [Epub ahead of print]535 30-45
    Immunoglobulin G glycans - Biomarkers and molecular effectors of aging.
    Jasminka Krištić, Gordan Lauc, Marija Pezer.
      Immunoglobulin G (IgG) antibodies are post-translationally modified by the addition of complex carbohydrate molecules - glycans, which have profound effects on the IgG function, most significantly as modulators of its inflammatory capacity. Therefore, it is not surprising that the changes in IgG glycosylation pattern are associated with various physiological states and diseases, including aging and age-related diseases. Importantly, within the inflammaging concept, IgG glycans are considered not only biomarkers but one of the molecular effectors of the aging process. The exact mechanism by which they exert their function, however, remains unknown. In this review, we list and comment on, to our knowledge, all studies that examined changes in IgG glycosylation during aging in humans. We focus on the information obtained from studies on general population, but we also cover the insights obtained from studies of long-lived individuals and people with age-related diseases. We summarize the current knowledge on how levels of different IgG glycans change with age (i.e., the extent and direction of the change with age) and discuss the potential mechanisms and possible functional roles of changes in IgG glycopattern that accompany aging.
    Keywords:  Aging; Biomarker; Glycan; Inflammaging; immunoglobulin G
    DOI:  https://doi.org/10.1016/j.cca.2022.08.006
  12. Front Cell Dev Biol. 2022 ;10 943519
    Breaking the aging epigenetic barrier.
    Sweta Sikder, Ganesan Arunkumar, Daniel P Melters, Yamini Dalal.
      Aging is an inexorable event occurring universally for all organisms characterized by the progressive loss of cell function. However, less is known about the key events occurring inside the nucleus in the process of aging. The advent of chromosome capture techniques and extensive modern sequencing technologies have illuminated a rather dynamic structure of chromatin inside the nucleus. As cells advance along their life cycle, chromatin condensation states alter which leads to a different epigenetic landscape, correlated with modified gene expression. The exact factors mediating these changes in the chromatin structure and function remain elusive in the context of aging cells. The accumulation of DNA damage, reactive oxygen species and loss of genomic integrity as cells cease to divide can contribute to a tumor stimulating environment. In this review, we focus on genomic and epigenomic changes occurring in an aged cell which can contribute to age-related tumor formation.
    Keywords:  cancer; chromatin dynamics; histone variants; nucleosomes; senescence
    DOI:  https://doi.org/10.3389/fcell.2022.943519
  13. J Clin Invest. 2022 Aug 15. pii: e158451. [Epub ahead of print]132(16):
    Metabolic changes in aging humans: current evidence and therapeutic strategies.
    Allyson K Palmer, Michael D Jensen.
      Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.
    DOI:  https://doi.org/10.1172/JCI158451
  14. Brain Behav. 2022 Aug 15. e2736
    Molecular and histological correlates of cognitive decline across age in male C57BL/6J mice.
    Rachel Britton, Angela T Liu, Sanket V Rege, Julia M Adams, Lily Akrapongpisak, David Le, Raniel Alcantara-Lee, Raul A Estrada, Rebecca Ray, Sara Ahadi, Ian Gallager, Cindy F Yang, S Sakura Minami, Steven P Braithwaite, Eva Czirr, Meghan Kerrisk Campbell.
       INTRODUCTION: Increasing age is the number one risk factor for developing cognitive decline and neurodegenerative disease. Aged humans and mice exhibit numerous molecular changes that contribute to a decline in cognitive function and increased risk of developing age-associated diseases. Here, we characterize multiple age-associated changes in male C57BL/6J mice to understand the translational utility of mouse aging.
    METHODS: Male C57BL/6J mice from various ages between 2 and 24 months of age were used to assess behavioral, as well as, histological and molecular changes across three modalities: neuronal, microgliosis/neuroinflammation, and the neurovascular unit (NVU). Additionally, a cohort of 4- and 22-month-old mice was used to assess blood-brain barrier (BBB) breakdown. Mice in this cohort were treated with a high, acute dose of lipopolysaccharide (LPS, 10 mg/kg) or saline control 6 h prior to sacrifice followed by tail vein injection of 0.4 kDa sodium fluorescein (100 mg/kg) 2 h later.
    RESULTS: Aged mice showed a decline in cognitive and motor abilities alongside decreased neurogenesis, proliferation, and synapse density. Further, neuroinflammation and circulating proinflammatory cytokines were increased in aged mice. Additionally, we found changes at the BBB, including increased T cell infiltration in multiple brain regions and an exacerbation in BBB leakiness following chemical insult with age. There were also a number of readouts that were unchanged with age and have limited utility as markers of aging in male C57BL/6J mice.
    CONCLUSIONS: Here we propose that these changes may be used as molecular and histological readouts that correspond to aging-related behavioral decline. These comprehensive findings, in the context of the published literature, are an important resource toward deepening our understanding of normal aging and provide an important tool for studying aging in mice.
    Keywords:  T lymphocytes; aging; behavior; blood-brain barrier; hippocampus; neuroinflammation
    DOI:  https://doi.org/10.1002/brb3.2736
  15. Aging Cell. 2022 Aug 19. e13666
    Rapamycin/metformin co-treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice.
    Peter C Reifsnyder, Kevin Flurkey, Rosalinda Doty, Nigel A Calcutt, Robert A Koza, David E Harrison.
      Rapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/LtJ (NcZ10). Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30 weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA-IR, and inflammation, and prevented hyperinsulinemia and pre-steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c-reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulin-resistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (Mest, Gpam), inflammation (Itgam, Itgax, Hmox1, Lbp), and cell senescence (Serpine1). In liver, the addition of metformin counteracted rapamycin-induced alterations of G6pc, Ppara, and Ldlr expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic Fasn expression, potentially preventing lipidosis. These results delineate a state of "insulin signaling restriction" that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the development of its comorbidities. Our results are relevant for the treatment of T2D, the optimization of current rapamycin-based treatments for posttransplant rejection and various cancers, and for the development of treatments for healthy aging.
    Keywords:  diabetic complications; insulin sensitivity; metformin; mice; rapamycin; type 2 diabetes
    DOI:  https://doi.org/10.1111/acel.13666
  16. Mol Cells. 2022 Aug 19.
    Transcriptional Heterogeneity of Cellular Senescence in Cancer.
    Muhammad Junaid, Aejin Lee, Jaehyung Kim, Tae Jun Park, Su Bin Lim.
      Cellular senescence plays a paradoxical role in tumorigenesis through the expression of diverse senescence-associated (SA) secretory phenotypes (SASPs). The heterogeneity of SA gene expression in cancer cells not only promotes cancer stemness but also protects these cells from chemotherapy. Despite the potential correlation between cancer and SA biomarkers, many transcriptional changes across distinct cell populations remain largely unknown. During the past decade, single-cell RNA sequencing (scRNA-seq) technologies have emerged as powerful experimental and analytical tools to dissect such diverse senescence-derived transcriptional changes. Here, we review the recent sequencing efforts that successfully characterized scRNA-seq data obtained from diverse cancer cells and elucidated the role of senescent cells in tumor malignancy. We further highlight the functional implications of SA genes expressed specifically in cancer and stromal cell populations in the tumor microenvironment. Translational research leveraging scRNA-seq profiling of SA genes will facilitate the identification of novel expression patterns underlying cancer susceptibility, providing new therapeutic opportunities in the era of precision medicine.
    Keywords:  cancer; cellular heterogeneity; senescence; single-cell RNA sequencing
    DOI:  https://doi.org/10.14348/molcells.2022.0036
  17. Elife. 2022 Aug 18. pii: e80169. [Epub ahead of print]11
    Artificially stimulating retrotransposon activity increases mortality and accelerates a subset of aging phenotypes in Drosophila.
    Joyce Rigal, Ane Martin Anduaga, Elena Bitman, Emma Rivellese, Sebastian Kadener, Michael T Marr.
      Transposable elements (TE) are mobile sequences of DNA that can become transcriptionally active as an animal ages. Whether TE activity is simply a byproduct of heterochromatin breakdown or can contribute towards the aging process is not known. Here we place the TE gypsy under the control of the UAS GAL4 system to model TE activation during aging. We find that increased TE activity shortens the lifespan of male D. melanogaster. The effect is only apparent in middle aged animals. The increase in mortality is not seen in young animals. An intact reverse transcriptase is necessary for the decrease in lifespan implicating a DNA mediated process in the effect. The decline in lifespan in the active gypsy flies is accompanied by the acceleration of a subset of aging phenotypes. TE activity increases sensitivity to oxidative stress and promotes a decline in circadian rhythmicity. The overexpression of the Forkhead-box O family (FOXO) stress response transcription factor can partially rescue the detrimental effects of increased TE activity on lifespan. Our results provide evidence that active TEs can behave as effectors in the aging process and suggest a potential novel role for dFOXO in its promotion of longevity in D. melanogaster.
    Keywords:  D. melanogaster; chromosomes; gene expression
    DOI:  https://doi.org/10.7554/eLife.80169
  18. Aging Cell. 2022 Aug 18. e13692
    B cell-intrinsic changes with age do not impact antibody-secreting cell formation but delay B cell participation in the germinal centre reaction.
    Jia Le Lee, Sigrid C Fra-Bido, Alice R Burton, Silvia Innocentin, Danika L Hill, Michelle A Linterman.
      Vaccines typically protect against (re)infections by generating pathogen-neutralising antibodies. However, as we age, antibody-secreting cell formation and vaccine-induced antibody titres are reduced. Antibody-secreting plasma cells differentiate from B cells either early post-vaccination through the extrafollicular response or from the germinal centre (GC) reaction, which generates long-lived antibody-secreting cells. As the formation of both the extrafollicular antibody response and the GC requires the interaction of multiple cell types, the impaired antibody response in ageing could be caused by B cell intrinsic or extrinsic factors, or a combination of the two. Here, we show that B cells from older people do not have intrinsic defects in their proliferation and differentiation into antibody-secreting cells in vitro compared to those from the younger donors. However, adoptive transfer of B cells from aged mice to young recipient mice showed that differentiation into extrafollicular plasma cells was favoured at the expense of B cells entering the GC during the early stages of GC formation. In contrast, by the peak of the GC response, GC B cells derived from the donor cells of aged mice had expanded to the same extent as those from the younger donors. This indicates that age-related intrinsic B cell changes delay the GC response but are not responsible for the impaired antibody-secreting response or smaller peak GC response in ageing. Collectively, this study shows that B cells from aged individuals are not intrinsically defective in responding to stimulation and becoming antibody-secreting cells, implicating B cell-extrinsic factors as the primary cause of age-associated impairment in the humoral immunity.
    Keywords:  B cells; ageing; antibodies; vaccine response
    DOI:  https://doi.org/10.1111/acel.13692
  19. Aging Cell. 2022 Aug 17. e13693
    Reduced bone morphogenic protein signaling along the gut-neuron axis by heat shock factor promotes longevity.
    Sonja L B Arneaud, Jacob McClendon, Lexus Tatge, Abigail Watterson, Kielen R Zuurbier, Bhoomi Madhu, Tina L Gumienny, Peter M Douglas.
      Aging is a complex and highly regulated process of interwoven signaling mechanisms. As an ancient transcriptional regulator of thermal adaptation and protein homeostasis, the Heat Shock Factor, HSF-1, has evolved functions within the nervous system to control age progression; however, the molecular details and signaling dynamics by which HSF-1 modulates age across tissues remain unclear. Herein, we report a nonautonomous mode of age regulation by HSF-1 in the Caenorhabditis elegans nervous system that works through the bone morphogenic protein, BMP, signaling pathway to modulate membrane trafficking in peripheral tissues. In particular, HSF-1 represses the expression of the neuron-specific BMP ligand, DBL-1, and initiates a complementary negative feedback loop within the intestine. By reducing receipt of DBL-1 in the periphery, the SMAD transcriptional coactivator, SMA-3, represses the expression of critical membrane trafficking regulators including Rab GTPases involved in early (RAB-5), late (RAB-7), and recycling (RAB-11.1) endosomal dynamics and the BMP receptor binding protein, SMA-10. This reduces cell surface residency and steady-state levels of the type I BMP receptor, SMA-6, in the intestine and further dampens signal transmission to the periphery. Thus, the ability of HSF-1 to coordinate BMP signaling along the gut-brain axis is an important determinate in age progression.
    Keywords:  BMP signaling; HSF-1; Rab GTPases; SMAD; TGF-β; aging; endocytosis; gut-neuron axis; membrane traffic
    DOI:  https://doi.org/10.1111/acel.13693
  20. Exp Gerontol. 2022 Aug 16. pii: S0531-5565(22)00239-X. [Epub ahead of print] 111931
    Inflammaging: The ground for sarcopenia?
    Zejun Liang, Tianxiao Zhang, Honghong Liu, Zhenlin Li, Lihong Peng, Changyi Wang, Tiantian Wang.
      Sarcopenia is a progressive skeletal muscle disease that occurs most commonly in the elderly population, contributing to increased costs and hospitalization. Exercise and nutritional therapy have been proven to be effective for sarcopenia, and some drugs can also alleviate declines in muscle mass and function due to sarcopenia. However, there is no specific pharmacological treatment for sarcopenia at present. This review will mainly discuss the relationship between inflammaging and sarcopenia. The increased secretion of proinflammatory cytokines with aging may be because of cellular senescence, immunosenescence, alterations in adipose tissue, damage-associated molecular patterns (DAMPs), and gut microbes due to aging. These sources of inflammaging can impact the sarcopenia process through direct or indirect pathways. Conversely, sarcopenia can also aggravate the process of inflammaging, creating a vicious cycle. Targeting sources of inflammaging can influence muscle function, which could be considered a therapeutic target for sarcopenia. Moreover, not only proinflammatory cytokines but also anti-inflammatory cytokines can influence muscle and inflammation and participate in the progression of sarcopenia. This review focuses on the effects of TNF-α, IL-6, and IL-10, which can be detected in plasma. Therefore, clearing chronic inflammation by targeting proinflammatory cytokines (TNF-α, IL-1, IL-6) and the inflammatory pathway (JAK/STAT, autophagy, NF-κB) may be effective in treating sarcopenia.
    Keywords:  Anti-inflammatory cytokines; Inflammaging; Proinflammatory cytokines; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2022.111931
  21. Aging (Albany NY). 2022 Aug 13. undefined(undefined):
    T cell senescence by N-glycan branching.
    Haik Mkhikian, Michael Demetriou.
      
    Keywords:  N-acetylglucosamine; N-glycan branching; T cell; immune-senescence; interleukin-7
    DOI:  https://doi.org/10.18632/aging.204239
  22. Mutat Res Rev Mutat Res. 2022 Aug 12. pii: S1383-5742(22)00030-8. [Epub ahead of print] 108440
    Interplay of cGAS with micronuclei: regulation and diseases.
    Xihan Guo, Henning Hintzsche, Weijiang Xu, Juan Ni, Jinglun Xue, Xu Wang.
      In higher eukaryotes, sophisticate regulation of genome function requires all chromosomes to be packed into a single nucleus. Micronucleus (MN), the dissociative nucleus-like structure frequently observed in aging and multiple disease settings, has critical, yet under-recognized, pathophysiological functions. Micronuclei (MNi) have recently emerged as major sources of cytosolic DNA that can activate the cGAS-STING axis in a cell-intrinsic manner. However, MNi induced from different genotoxic stressors display great heterogeneity in binding or activating cGAS and the signaling responses downstream of the MN-induced cGAS-STING axis have divergent outcomes including autoimmunity, autoinflammation, metastasis, or cell death. Thus, full characterization of molecular network underpinning the interplay of cGAS and MN is important to elucidate the pathophysiological roles of immunogenic MN and design improved drugs that selectively target cancer via boosting the MN-derived cGAS-STING axis. Here, we summarize our current understanding of the mechanisms for self-DNA discrimination by cGAS. We focus on discussing how MN immunogencity is dictated by multiple mechanisms including integrity of micronuclear envelope, state of nucleosome and DNA, competitive factors, damaged mitochondrial DNA and micronucleophagy. We also describe emerging links between immunogenic MN and human diseases including cancer, neurodegenerative diseases and COVID-19. Particularly, we explore the exciting concept of inducing immunogenic MN as a therapeutic approach in treating cancer. We propose a new theoretical framework to describe immunogenic MN as a biological sensor to modulate cellular processes in response to genotoxic stress and provide perspectives on developing novel experimental approaches to unravel the complexity of MN immunogenicity regulation and immunogenic MN pathophysiology.
    Keywords:  Autoimmunity; COVID-19; Cancer; Inflammation; Metastasis; Neurodegenerative disease
    DOI:  https://doi.org/10.1016/j.mrrev.2022.108440
  23. Front Cell Dev Biol. 2022 ;10 955612
    Thermogenic adipose tissue aging: Mechanisms and implications.
    Graciano da Nadyellem Silva, Angelica Amorim Amato.
      Adipose tissue undergoes significant anatomical and functional changes with aging, leading to an increased risk of metabolic diseases. Age-related changes in adipose tissue include overall defective adipogenesis, dysfunctional adipokine secretion, inflammation, and impaired ability to produce heat by nonshivering thermogenesis. Thermogenesis in adipose tissue is accomplished by brown and beige adipocytes, which also play a role in regulating energy homeostasis. Brown adipocytes develop prenatally, are found in dedicated depots, and involute in early infancy in humans. In contrast, beige adipocytes arise postnatally in white adipose tissue and persist throughout life, despite being lost with aging. In recent years, there have been significant advances in the understanding of age-related reduction in thermogenic adipocyte mass and function. Mechanisms underlying such changes are beginning to be delineated. They comprise diminished adipose precursor cell pool size and adipogenic potential, mitochondrial dysfunction, decreased sympathetic signaling, and altered paracrine and endocrine signals. This review presents current evidence from animal models and human studies for the mechanisms underlying thermogenic adipocyte loss and discusses potential strategies targeting brown and beige adipocytes to increase health span and longevity.
    Keywords:  aging; beige adipocyte; brown adipocyte; senescence; thermogenic adipose tissue
    DOI:  https://doi.org/10.3389/fcell.2022.955612
  24. Emed Res. 2021 ;pii: 100020. [Epub ahead of print]3
    Therapeutic Targeting of Histone Deacetylation to Prevent Alzheimer's Disease.
    Sophia Chacko, Warren Ladiges.
      Efforts to find disease-modifying treatments for Alzheimer's disease (AD) have been largely unsuccessful. The relative lack of progress and the age-related incidence of AD suggest that modulation of aging per se may be a useful alternative treatment approach. Therapeutics aimed at preventing or reversing aging should be effective in preventing or reversing dementia and the pathology associated with progressive AD. Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. HDAC activity becomes dysregulated with age and in AD. An intriguing concept is that HDAC inhibition effectively forestalls AD pathology measured more broadly, addressing the notion that rectifying homeostatic gene expression may be the critical step in ameliorating AD pathogenesis at the earliest stage of disease initiation. HDAC inhibitors target several pathways associated with aging and AD neuropathology including loss of synaptic function, mitochondrial dysfunction, increased oxidative stress, and decreased autophagy activity. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and provide pathways for treating AD.
    Keywords:  Alzheimer’s disease; geroscience; histone deacetylation; histone deactylase inhibitors
  25. J Virol. 2022 Aug 17. e0108122
    Herpes Simplex Virus Type 1 Preferentially Enhances Neuro-Inflammation and Senescence in Brainstem of Female Mice.
    Mahesh Kumar Sivasubramanian, Raisa Monteiro, Kelly S Harrison, Bhuvana Plakkot, Madhan Subramanian, Clinton Jones.
      Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. The latency associated transcript (LAT) is the only viral gene abundantly expressed during latency. Wild-type (WT) HSV-1 reactivates more efficiently than LAT mutants because LAT promotes establishment and maintenance of latency. While sensory neurons in trigeminal ganglia (TG) are important sites for latency, brainstem is also a site for latency and reactivation from latency. The principal sensory nucleus of the spinal trigeminal tract (Pr5) likely harbors latent HSV-1 because it receives afferent inputs from TG. The locus coeruleus (LC), an adjacent brainstem region, sends axonal projections to cortical structures and is indirectly linked to Pr5. Senescent cells accumulate in the nervous system during aging and accelerate neurodegenerative processes. Generally senescent cells undergo irreversible cell cycle arrest and produce inflammatory cytokines and chemokines. Based on these observations, we hypothesized HSV-1 influences senescence and inflammation in Pr5 and LC of latently infected mice. This hypothesis was tested using a mouse model of infection. Strikingly, female but not age-matched male mice latently infected with a LAT null mutant (dLAT2903) exhibited significantly higher levels of senescence markers and inflammation in LC, including cell cycle inhibitor p16, NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), IL-1α, and IL-β. Conversely, Pr5 in female but not male mice latently infected with WT HSV-1 or dLAT2903 exhibited enhanced expression of important inflammatory markers. The predilection of HSV-1 to induce senescence and inflammation in key brainstem regions of female mice infers that enhanced neurodegeneration occurs. IMPORTANCE HSV-1 (herpes simplex virus 1), an important human pathogen, establishes lifelong latency in neurons in trigeminal ganglia and the central nervous system. In contrast to productive infection, the only viral transcript abundantly expressed in latently infected neurons is the latency associated transcript (LAT). The brainstem, including principal sensory nucleus of the spinal trigeminal tract (Pr5) and locus coeruleus (LC), may expedite HSV-1 spread from trigeminal ganglia to the brain. Enhanced senescence and expression of key inflammatory markers were detected in LC of female mice latently infected with a LAT null mutant (dLAT2903) relative to age-matched male or female mice latently infected with wild-type HSV-1. Conversely, wild-type HSV-1 and dLAT2903 induced higher levels of senescence and inflammatory markers in Pr5 of latently infected female mice. In summary, enhanced inflammation and senescence in LC and Pr5 of female mice latently infected with HSV-1 are predicted to accelerate neurodegeneration.
    Keywords:  HSV-1; LAT; brainstem; immune senescence; inflammation; latency
    DOI:  https://doi.org/10.1128/jvi.01081-22
  26. Neuro Oncol. 2022 Aug 17. pii: noac199. [Epub ahead of print]
    BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
    Florian Selt, Romain Sigaud, Gintvile Valinciute, Philipp Sievers, Julia Zaman, Clara Alco, Simone Schmid, Heike Peterziel, Jessica W Tsai, Romain Guiho, Juan Pedro Martínez-Barbera, Stefan Pusch, Jing Deng, Yifan Zhai, Cornelis M van Tilburg, Martin U Schuhman, Ahmed E L Damaty, Pratiti Bandopadhayay, Christel Herold-Mende, Andreas von Deimling, Stefan M Pfister, Joan Montero, David Capper, Ina Oehme, Felix Sahm, David T W Jones, Olaf Witt, Till Milde.
       BACKGROUND: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and a mitogen-activated protein kinase (MAPK)-driven disease. Oncogenic MAPK-signaling drives the majority of cells into oncogene-induced senescence (OIS). While OIS induces resistance to anti-proliferative therapies, it represents a potential vulnerability exploitable by senolytic agents.
    METHODS: We established new patient-derived PA cell lines that preserve molecular features of the primary tumors and can be studied in OIS and proliferation depending on expression ore repression of the SV40 large T antigen. We determined expression of anti-apoptotic BCL-2 members in these models and primary PA. Dependence of senescent PA cells on anti-apoptotic BCL-2 members was investigated using a comprehensive set of BH3-mimetics.
    RESULTS: Senescent PA cells upregulate BCL-XL upon senescence induction and show dependency on BCL-XL for survival. BH3 mimetics with high affinity for BCL-XL (BCL-XLi) reduce metabolic activity and induce mitochondrial apoptosis in senescent PA cells at nano-molar concentrations. In contrast, BH3 mimetics without BCL-XLi activity, conventional chemotherapy and MEK inhibitors show no effect.
    CONCLUSIONS: Our data demonstrates that BCL-XL is critical for survival of senescent PA tumor cells and provides proof-of-principle for the use of clinically available BCL-XL-dependent senolytics.
    Keywords:  BCL-XL; BH3 mimetics; oncogene-induced senescence; pilocytic astrocytoma
    DOI:  https://doi.org/10.1093/neuonc/noac199
  27. J Clin Invest. 2022 Aug 15. pii: e158446. [Epub ahead of print]132(16):
    Epigenetics, DNA damage, and aging.
    Carolina Soto-Palma, Laura J Niedernhofer, Christopher D Faulk, Xiao Dong.
      Over the course of a human lifespan, genome integrity erodes, leading to an increased abundance of several types of chromatin changes. The abundance of DNA lesions (chemical perturbations to nucleotides) increases with age, as does the number of genomic mutations and transcriptional disruptions caused by replication or transcription of those lesions, respectively. At the epigenetic level, precise DNA methylation patterns degrade, likely causing increasingly stochastic variations in gene expression. Similarly, the tight regulation of histone modifications begins to unravel. The genomic instability caused by these mechanisms allows transposon element reactivation and remobilization, further mutations, gene dysregulation, and cytoplasmic chromatin fragments. This cumulative genomic instability promotes cell signaling events that drive cell fate decisions and extracellular communications known to disrupt tissue homeostasis and regeneration. In this Review, we focus on age-related epigenetic changes and their interactions with age-related genomic changes that instigate these events.
    DOI:  https://doi.org/10.1172/JCI158446
  28. Curr Cancer Drug Targets. 2022 Aug 16.
    Characteristic Hallmarks of Aging and the Impact on Carcinogenesis.
    Sergio Terracina, Giampiero Ferraguti, Carla Petrella, Sabina Maria Bruno, Giovanna Blaconà, Maria Grazia Di Certo, Antonio Minni, Antonio Greco, Angela Musacchio, Massimo Ralli, Luigi Tarani, Mauro Ceccanti, Antonella Polimeni, Viviana Triaca, Marco Fiore.
      Evidence shows that there is a synergistic, bidirectional association between cancer and aging with many shared traits. Age itself is a risk factor for the onset of most cancers while evidence suggests that cancer and its treatments might accelerate aging by causing genotoxic and cytotoxic insults. Aging has been associated with a series of alterations that can be linked to cancer: i) genomic instability caused by DNA damage or epigenetic alterations coupled with repair errors, which lead to progressive accumulation of mutations; ii) telomere attrition with possible impairment of telomerase, shelterin complex, or the trimeric complex (Cdc13, Stn1 and Ten1 - CST) activities associated with abnormalities in DNA replication and repair; iii) altered proteostasis especially when leading to an augmented proteasome, chaperon and autophagy-lysosome activity; iv) mitochondrial dysfunction causing oxidative stress; v) cellular senescence; vi) stem cells exhaustion, intercellular altered communication and deregulated nutrient sensing which are associated with microenvironmental modifications which may facilitate the subsequential role of cancer stem cells. Nowadays anti-growth factor agents and epigenetic therapies seem to assume an increasing role to fight aging-related diseases, especially cancer. This report aims to discuss the impact of age on cancer growth.
    Keywords:  aging; cancer; epigenetic; genomic instability; microenvironment; oxidative stress.
    DOI:  https://doi.org/10.2174/1568009622666220816120353
  29. J Gerontol A Biol Sci Med Sci. 2022 Aug 17. pii: glac135. [Epub ahead of print]
    Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.
    Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar.
       BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.
    METHODS: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure.
    RESULTS: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects.
    CONCLUSION: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.
    Keywords:  Clinical trials; GlyNAC; Metabolism; Oxidative stress; Successful aging
    DOI:  https://doi.org/10.1093/gerona/glac135
  30. Immunity. 2022 Aug 10. pii: S1074-7613(22)00340-5. [Epub ahead of print]
    The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging.
    Seungjin Ryu, Sviatoslav Sidorov, Eric Ravussin, Maxim Artyomov, Akiko Iwasaki, Andrew Wang, Vishwa Deep Dixit.
      The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.
    Keywords:  SPARC; TLR4; caloric restriction; inflammation; interferon-stimulated gene; macrophage; matricellular protein
    DOI:  https://doi.org/10.1016/j.immuni.2022.07.007
  31. Acta Pharm Sin B. 2022 Aug;12(8): 3255-3262
    CXCR6-based immunotherapy in autoimmune, cancer and inflammatory infliction.
    Tingting Li, Jie Pan, Hongqi Chen, Yongliang Fang, Yang Sun.
      T cells, including both CD4+ and CD8+ T cells, play a pivotal role in mediating various inflammation and immune disorders. A long-standing challenge in T cell-based immunotherapy is to precisely inactivate or delete the pathogenic T cells in inflammation and autoimmune diseases, or to selectively expand the immunocompetent T cell in tumor or other immune compromised situations, without inducing global immunosuppression or zealous immune activation respectively. To achieve this, a specific marker is needed to differentiate the pathogenic or immunocompetent T cell among the rests. Indeed, recent progress of immunology strongly suggests that CXC chemokine receptor 6 (CXCR6, CD186) is such a kind of marker. Here, we review the emerging role of CXCR6 as a novel target for immunotherapy and discuss the underlying mechanism. We propose that CXCR6-based immunotherapy will play a significant role in autoimmune, nonalcoholic steatohepatitis (NASH), tumor, coronavirus disease 2019 (COVID-19) and even ageing-related inflammatory infliction.
    Keywords:  Autoimmune diseases; COVID-19; CXCL16; CXCR6; Immunotherapy; Inflammation; Nonalcoholic steatohepatitis; Tumor
    DOI:  https://doi.org/10.1016/j.apsb.2022.03.012
  32. Aging Cell. 2022 Aug 13. e13691
    Nitric oxide-soluble guanylyl cyclase pathway as a contributor to age-related memory impairment in Drosophila.
    Ayako Tonoki, Saki Nagai, Zhihua Yu, Tong Yue, Sizhe Lyu, Xue Hou, Kotomi Onuki, Kaho Yabana, Hiroki Takahashi, Motoyuki Itoh.
      Age-related changes in the transcriptome lead to memory impairment. Several genes have been identified to cause age-dependent memory impairment (AMI) by changes in their expression, but genetic screens to identify genes critical for AMI have not been performed. The fruit fly is a useful model for studying AMI due to its short lifespan and the availability of consistent techniques and environments to assess its memory ability. We generated a list of candidate genes that act as AMI regulators by performing a comprehensive analysis of RNAsequencing data from young and aged fly heads and genome-wide RNAi screening data to identify memory-regulating genes. A candidate screen using temporal and panneuronal RNAi expression was performed to identify genes critical for AMI. We identified the guanylyl cyclase β-subunit at 100B (gycβ) gene, which encodes a subunit of soluble guanylyl cyclase (sGC), the only intracellular nitric oxide (NO) receptor in fruit flies, as a negative regulator of AMI. RNAi knockdown of gycβ in neurons and NO synthase (NOS) in glia or neurons enhanced the performance of intermediate-term memory (ITM) without apparent effects on memory acquisition. We also showed that pharmacological inhibition of sGC and NOS enhanced ITM in aged individuals, suggesting the possibility that age-related enhancement of the NO-sGC pathway causes memory impairment.
    Keywords:   Drosophila ; aging; glia; memory; nitric oxide; soluble guanylyl cyclase
    DOI:  https://doi.org/10.1111/acel.13691
  33. J Pharm Pharmacol. 2022 Aug 16. pii: rgac051. [Epub ahead of print]
    Glycation-induced age-related illnesses, antiglycation and drug delivery strategies.
    Hamdy Abdelkader, Wesam W Mustafa, Ali M Alqahtani, Sultan Alsharani, Adel Al Fatease, Raid G Alany.
       OBJECTIVES: Ageing is a major cause of multiple age-related diseases. Several mechanisms have been reported to contribute to these abnormalities including glycation, oxidative stress, the polyol pathway and osmotic stress. Glycation, unlike glycosylation, is an irregular biochemical reaction to the formation of active advanced glycation end-products (AGEs), which are considered to be one of the causes of these chronic diseases. This study provides a recent and comprehensive review on the possible causes, mechanisms, types, analytical techniques, diseases and treatments of the toxic glycation end products.
    KEY FINDINGS: Several mechanisms have been found to play a role in generating hyperglycaemia-induced oxidative stress including an increase in the levels of reactive oxygen species (ROS), increase in the levels of AGEs, binding of AGEs and their receptors (RAGE) and the polyol pathway and thus have been investigated as promising novel targets.
    SUMMARY: This review focuses on the key mechanisms attributed to cumulative increases of glycation and pathological RAGE expression as a significant cause of multiple age-related diseases, and reporting on different aspects of antiglycation therapy as a novel approach to managing/treating age-related diseases. Additionally, historical, current and possible future antiglycation approaches will be presented focussing on novel drug delivery methods.
    Keywords:  Maillard reaction; drug repurposing; flavonoids; glycation; nanotechnology; polyphenols
    DOI:  https://doi.org/10.1093/jpp/rgac051
  34. Exp Ther Med. 2022 Sep;24(3): 545
    Ginsenoside Rg1 ameliorates apoptosis, senescence and oxidative stress in ox-LDL-induced vascular endothelial cells via the AMPK/SIRT3/p53 signaling pathway.
    Tian-Jiao Lyu, Zi-Xiu Zhang, Jun Chen, Zong-Jun Liu.
      Coronary heart disease (CHD) mainly refers to coronary atherosclerotic heart disease and its pathogenesis is complex. Ginsenoside Rg1 (Rg1) has a wide range of pharmacological activities, such as antitumor effects, enhancing immunity and exerting protective effects on the vascular system. In the present study, the effect of Rg1 on vascular endothelial cells in CHD was investigated. Oxidized low-density lipoprotein (ox-LDL) was used to induce human umbilical vein endothelial cells (HUVECs) and cells were treated with 1, 5 or 10 µM Rg1. Cell Counting Kit-8 assay, TUNEL staining, western blot analysis of apoptosis-related proteins and senescence-related proteins, senescence-associated β-galactosidase staining, ELISA and other techniques including related kits of oxidative stress markers were used to detect the viability, apoptosis, oxidative stress, inflammatory cytokines including IL-1β, IL-6 and TNF-α and senescence of ox-LDL-induced HUVECs induced by Rg1. Western blot analysis was used to detect the expression levels of the AMP-activated protein kinase (AMPK)/sirtuin 3 (SIRT3)/p53 signaling pathway-related proteins. In addition, the associated mechanism was further determined using the AMPK pathway inhibitor compound C (CC). Rg1 increased the viability, and inhibited the apoptosis, senescence, oxidative stress and inflammation of ox-LDL-induced HUVECs. Pretreatment with CC partially reversed the protective effect of Rg1 on ox-LDL-induced HUVECs. In conclusion, Rg1 ameliorated apoptosis, senescence and oxidative stress of ox-LDL-induced HUVECs, at least in part, via the AMPK/SIRT3/p53 signaling pathway.
    Keywords:  AMP-activated protein kinase/sirtuin 3/p53 signaling pathway; apoptosis; ginsenoside Rg1; oxidative stress; oxidized low-density lipoprotein; senescence; vascular endothelial cell
    DOI:  https://doi.org/10.3892/etm.2022.11482
  35. Can J Physiol Pharmacol. 2022 Aug 19.
    Nicotinamide adenine dinucleotide attenuates acetaminophen-induced acute liver injury via activation of PARP1, Sirt1, and Nrf2 in mice.
    Cuiting Liao, Li Zhang, Rong Jiang, Da Hu, Juanjuan Xu, Kai Hu, Shifang Jiang, Longhui Li, Yongqiang Yang, Jiayi Huang, Li Tang, Longjiang Li.
      The aim of this study was to investigate the protective effect of nicotinamide adenine dinucleotide (NAD+) against acute liver injury (ALI) induced by acetaminophen (APAP) overdose in mice. First, serum transaminases were used to assess the protective effect of NAD+, and the data revealed that NAD+ mitigated the APAP-induced ALI in a dose-dependent manner. Then, we performed hematoxylin-eosin staining of liver tissues and found that NAD+ alleviated the abnormalities of histopathology. Meanwhile, increase in the malondialdehyde content and decrease in glutathione, superoxide dismutase (SOD), and glutathione peroxidase were identified in the APAP group, which were partially prevented by the NAD+ pretreatment. Moreover, compared with the mice treated with APAP only, the expression of poly ADP-ribose polymerase 1 (PARP1), Sirtuin1 (Sirt1), SOD2, nuclear factor erythroid 2-related factor 2 (Nrf2), and hemoxygenase-1 was upregulated, while Kelch-like ECH-associated protein 1 and histone H2AX phosphorylated on Ser-139 were downregulated by NAD+ in NAD+ + APAP group. Conversely, NAD+ could not correct the elevated expression of phospho-Jun N-terminal kinase and phospho-extracellular signal-regulated kinase induced by APAP. Taken together, these findings suggest that NAD+ confers an anti-ALI effect to enhance the expression of PARP1 and Sirt1, and to simultaneously stimulate the Nrf2 anti-oxidant signaling pathway.
    Keywords:  Nrf2; PARP1; Sirt1; acetaminophen; acétaminophène; nicotinamide adenine dinucleotide; nicotinamide adénine dinucléotide
    DOI:  https://doi.org/10.1139/cjpp-2022-0127
  36. Aging Cell. 2022 Aug 19. e13694
    Adaptive cellular response of the substantia nigra dopaminergic neurons upon age-dependent iron accumulation.
    Kujin Kwon, Hwapyeong Cho, Soyeon Lee, Eun Jeong Cho, Weonjin Yu, Catherine Yen Li Kok, Hyunsoo Shawn Je, Jae-Ick Kim, Hyung Joon Cho, Taejoon Kwon.
      Progressive iron accumulation in the substantia nigra in the aged human brain is a major risk factor for Parkinson's disease and other neurodegenerative diseases. Heavy metals, such as iron, produce reactive oxygen species and consequently oxidative stress in cells. It is unclear, however, how neurons in the substantia nigra are protected against the age-related, excessive accumulation of iron. In this study, we examined the cellular response of the substantia nigra against age-related iron accumulation in rats of different ages. Magnetic resonance imaging confirmed the presence of iron in 6-month-old rats; in 15-month-old rats, iron accumulation significantly increased, particularly in the midbrain. Transcriptome analysis of the region, in which iron deposition was observed, revealed an increase in stress response genes in older animals. To identify the genes related to the cellular response to iron, independent of neurodevelopment, we exposed the neuroblastoma cell line SH-SY5Y to a similar quantity of iron and then analyzed their transcriptomic responses. Among various stress response pathways altered by iron overloading in the rat brain and SH-SY5Y cells, the genes associated with topologically incorrect protein responses were significantly upregulated. Knockdown of HERPUD1 and CLU in this pathway increased susceptibility to iron-induced cellular stress, thus demonstrating their roles in preventing iron overload-induced toxicity. The current study details the neuronal response to excessive iron accumulation, which is associated with age-related neurodegenerative diseases.
    Keywords:   substantia nigra ; aging; iron accumulation; iron toxicity; magnetic resonance imaging; transcriptome
    DOI:  https://doi.org/10.1111/acel.13694
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:28.