bims-senagi 2022-06-05 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022‒06‒05
nineteen papers selected by
Maria Grazia Vizioli
Mayo Clinic

NF-κB-dependent secretome of senescent cells can trigger neuroendocrine transdifferentiation of breast cancer cells.
The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities.
TNF-α/IFN-γ synergy amplifies senescence-associated inflammation and SARS-CoV-2 receptor expression via hyper-activated JAK/STAT1.
Senescence-mediated anticancer effects of quercetin.
MAPK15 protects from oxidative stress-dependent cellular senescence by inducing the mitophagic process.
Rejuvenation of neutrophils and their extracellular vesicles is associated with enhanced aged fracture healing.
Ginsenoside Rg1 suppresses paraquat-induced epithelial cell senescence by enhancing autophagy in an ATG12-dependent manner.
Role of MicroRNAs in acceleration of vascular endothelial senescence.
Stem Cell-derived Exosomal MicroRNA as Therapy for Vascular Age-related Diseases.
Selective Growth Suppressive Effect of Pravastatin on Senescent Human Lung Fibroblasts.
Hyperbaric oxygen therapy for healthy aging: From mechanisms to therapeutics.
NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities.
Lifelong cytomegalovirus and early-LIFE irradiation synergistically potentiate age-related defects in response to vaccination and infection.
Inflammatory Microenvironment Accelerates Bone Marrow Mesenchymal Stem Cell Aging.
Acid-sensitive ion channel 1a mediates osteoarthritis chondrocyte senescence by promoting Lamin B1 degradation.
Genotype-Phenotype Correlation of T Cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer's Disease.
Co-Expression of TIGIT and Helios Marks Immunosenescent CD8+ T Cells During Aging.
The Hallmarks of Aging in Ataxia-Telangiectasia.
Fecal microbiota transplantation from young donor mice improves ovarian function in aged mice.

Aging Cell. 2022 Jun 02. e13632

NF-κB-dependent secretome of senescent cells can trigger neuroendocrine transdifferentiation of breast cancer cells.

Clotilde Raynard, Xingjie Ma, Anda Huna, Nolwenn Tessier, Amélie Massemin, Kexin Zhu, Jean-Michel Flaman, Florentin Moulin, Delphine Goehrig, Jean-Jacques Medard, David Vindrieux, Isabelle Treilleux, Hector Hernandez-Vargas, Sylvie Ducreux, Nadine Martin, David Bernard.

  Cellular senescence is characterized by a stable proliferation arrest in response to stresses and the acquisition of a senescence-associated secretory phenotype, called SASP, composed of numerous factors including pro-inflammatory molecules, proteases, and growth factors. The SASP affects the environment of senescent cells, especially during aging, by inducing and modulating various phenotypes such as paracrine senescence, immune cell activity, and extracellular matrix deposition and organization, which critically impact various pathophysiological situations, including fibrosis and cancer. Here, we uncover a novel paracrine effect of the SASP: the neuroendocrine transdifferentiation (NED) of some epithelial cancer cells, evidenced both in the breast and prostate. Mechanistically, this effect is mediated by NF-κB-dependent SASP factors, and leads to an increase in intracellular Ca2+ levels. Consistently, buffering Ca2+ by overexpressing the CALB1 buffering protein partly reverts SASP-induced NED, suggesting that the SASP promotes NED through a SASP-induced Ca2+ signaling. Human breast cancer dataset analyses support that NED occurs mainly in p53 WT tumors and in older patients, in line with a role of senescent cells and its secretome, as they are increasing during aging. In conclusion, our work, uncovering SASP-induced NED in some cancer cells, paves the way for future studies aiming at better understanding the functional link between senescent cell accumulation during aging, NED and clinical patient outcome.

Keywords:  aging; breast cancer; cellular senescence; neuroendocrine transdifferentiation; senescence-associated secretory phenotype

DOI:  https://doi.org/10.1111/acel.13632
Cell Biosci. 2022 May 31. 12(1): 74

The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities.

Yu Sun, Xia Wang, Tianwei Liu, Xiaoyan Zhu, Xudong Pan.

  BACKGROUND: The global population of older individuals is growing, and ageing is a key risk factor for atherosclerotic cardiovascular diseases. Abnormal accumulation of senescent cells can cause potentially deleterious effects on the organism with age. As a vital marker of cellular senescence, the senescence-associated secretory phenotype (SASP) is a novel mechanism to link cellular senescence with atherosclerosis.MAIN BODY: In this review, we concretely describe the characteristics of the SASP and its regulation mechanisms. Importantly, we provide novel perspectives on how the SASP can promote atherosclerosis. The SASP from different types of senescent cells have vital roles in atherosclerosis progression. As a significant mediator of the harmful effects of senescent cells, it can play a pro-atherogenic role by producing inflammation and immune dysfunction. Furthermore, the SASP can deliver senescence signals to the surrounding vascular cells, gradually contributing to the development of atherosclerosis. Finally, we focus on a variety of novel therapeutic strategies aimed to reduce the burden of atherosclerosis in elderly individuals by targeting senescent cells and inhibiting the regulatory mechanisms of the SASP.
CONCLUSION: This review systematically summarizes the multiple roles of the SASP in atherosclerosis and can contribute to the exploration of new therapeutic opportunities.

Keywords:  Ageing; Atherosclerosis; Inflammation; SASP; Senescent cell

DOI:  https://doi.org/10.1186/s13578-022-00815-5
Aging Cell. 2022 May 30. e13646

TNF-α/IFN-γ synergy amplifies senescence-associated inflammation and SARS-CoV-2 receptor expression via hyper-activated JAK/STAT1.

Renuka Kandhaya-Pillai, Xiaomeng Yang, Tamar Tchkonia, George M Martin, James L Kirkland, Junko Oshima.

  Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID-19 infection. The pathogenesis of COVID-19-related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS-CoV-2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF-α + IFN-γ or a cocktail of TNF-α + IFN-γ + IL-6, increased expression of ACE2/DPP4, accentuated the pro-inflammatory senescence-associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence-like state. IL-6 by itself failed to induce substantial effects on viral entry receptors or SASP-related genes, while synergy between TNF-α and IFN-γ initiated a positive feedback loop via hyper-activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper-inflammation, normalized SARS-CoV-2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine-mediated viral entry receptor activation and links with senescence and hyper-inflammation.

Keywords:  ACE2; COVID-19; DPP4; JAK-STAT; SARS-COV-2 receptor; cytokines; inflammation; senescence

DOI:  https://doi.org/10.1111/acel.13646
Nutr Res. 2022 May 10. pii: S0271-5317(22)00043-4. [Epub ahead of print]104 82-90

Senescence-mediated anticancer effects of quercetin.

Serpil Özsoy Gökbilen, Eda Becer, Hafize Seda Vatansever.

  Cellular senescence plays a key role in aging and age-related disease initiation. It is a highly dynamic and multistep process that can be stimulated by various stimuli, including cellular stress, DNA damage, telomere shortening, and oncogene activation. Also, senescence is a potent antitumor mechanism, by preventing the proliferation of cancerous cells. However, some of the senescent cells have apoptosis resistance and can cause recurrence in cancer. A new class of drugs termed senolytics selectively kill and eliminate senescent cells. In recent years, natural compounds such as quercetin have been discovered to be effective as senolytic agents. Quercetin is a phytochemical that has strong antioxidant properties and pro-apoptotic effects and has been investigated for many years. Additionally, it has great potential to be used as a senolytic agent. According to preclinical and early-phase clinical data of senolytic agent research, quercetin administration appears to be effective in preventing or alleviating cancer formation. In this paper, we review the importance of cellular senescence in carcinogenesis and the effects of quercetin on senescence, as well as quercetin's potential effects as a pro-apoptotic agent and suppressor of cancer cell proliferation.

Keywords:  Cancer prevention; Cellular senescence; Polyphenols; Proliferation; Quercetin

DOI:  https://doi.org/10.1016/j.nutres.2022.04.007
Aging Cell. 2022 Jun 01. e13620

MAPK15 protects from oxidative stress-dependent cellular senescence by inducing the mitophagic process.

Lorenzo Franci, Alessandro Tubita, Franca Maria Bertolino, Alessandro Palma, Giuseppe Cannino, Carmine Settembre, Andrea Rasola, Elisabetta Rovida, Mario Chiariello.

  Mitochondria are the major source of reactive oxygen species (ROS), whose aberrant production by dysfunctional mitochondria leads to oxidative stress, thus contributing to aging as well as neurodegenerative disorders and cancer. Cells efficiently eliminate damaged mitochondria through a selective type of autophagy, named mitophagy. Here, we demonstrate the involvement of the atypical MAP kinase family member MAPK15 in cellular senescence, by preserving mitochondrial quality, thanks to its ability to control mitophagy and, therefore, prevent oxidative stress. We indeed demonstrate that reduced MAPK15 expression strongly decreases mitochondrial respiration and ATP production, while increasing mitochondrial ROS levels. We show that MAPK15 controls the mitophagic process by stimulating ULK1-dependent PRKN Ser108 phosphorylation and inducing the recruitment of damaged mitochondria to autophagosomal and lysosomal compartments, thus leading to a reduction of their mass, but also by participating in the reorganization of the mitochondrial network that usually anticipates their disposal. Consequently, MAPK15-dependent mitophagy protects cells from accumulating nuclear DNA damage due to mitochondrial ROS and, consequently, from senescence deriving from this chronic DNA insult. Indeed, we ultimately demonstrate that MAPK15 protects primary human airway epithelial cells from senescence, establishing a new specific role for MAPK15 in controlling mitochondrial fitness by efficient disposal of old and damaged organelles and suggesting this kinase as a new potential therapeutic target in diverse age-associated human diseases.

Keywords:  MAP kinases; Oxidative DNA damage; autophagy; cellular senescence; mitophagy; signal transduction

DOI:  https://doi.org/10.1111/acel.13620
Aging Cell. 2022 Jun 03. e13651

Rejuvenation of neutrophils and their extracellular vesicles is associated with enhanced aged fracture healing.

Xin Zhang, Gurpreet Singh Baht, Rong Huang, Yu-Hsiu Chen, Kristin Happ Molitoris, Sara E Miller, Virginia Byers Kraus.

  Tissue repair is negatively affected by advanced age. Recent evidence indicates that hematopoietic cell-derived extracellular vesicles (EVs) are modulators of regenerative capacity. Here, we report that plasma EVs carrying specific surface markers indicate the degree of age-associated immunosenescence; moreover, this immunosenescence phenotype was accentuated by fracture injury. The number of CD11b+ Ly6Cintermediate Ly6Ghigh neutrophils significantly decreased with age in association with defective tissue regeneration. In response to fracture injury, the frequencies of neutrophils and associated plasma EVs were significantly higher in fracture calluses than in peripheral blood. Exposure of aged mice to youthful circulation through heterochronic parabiosis increased the number of neutrophils and their correlated Ly6G+ plasma EVs, which were associated with improved fracture healing in aged mice of heterochronic parabiosis pairs. Our findings create a foundation for utilizing specific immune cells and EV subsets as potential biomarkers and therapeutic strategies to promote resilience to stressors during aging.

Keywords:  age; extracellular vesicles; fracture healing; immune cells; immunosenescence; inflammaging; parabiosis; resilience

DOI:  https://doi.org/10.1111/acel.13651
Environ Toxicol. 2022 Jun 03.

Ginsenoside Rg1 suppresses paraquat-induced epithelial cell senescence by enhancing autophagy in an ATG12-dependent manner.

Changbao Huang, Xiang Xue, Nengkai Gong, Jinghan Jiang.

  Paraquat (PQ), as a widely used herbicide, is highly toxic to human. PQ-induced pulmonary fibrosis is the main reason for respiratory failure and death. In PQ-poisoned mice, we find abundant senescent epithelial cells in the lung tissues, which can contribute to the activation of pulmonary fibroblasts. Ginsenoside Rg1 (Rg1), the main active component of ginseng, possess beneficial properties against aging. In our work, we aimed to investigate the potential protective effects of Rg1 on PQ-induced pulmonary fibrosis and the underlying mechanism. In vivo, the treatment of Rg1 can attenuate PQ-induced pulmonary fibrosis and decrease senescence and senescence associated secretory phenotype (SASP) expression. In vitro, Rg1 can effectively eliminate senescent cells via apoptosis, but not normal cells. In addition, we demonstrate that Rg1 can enhance autophagy activity via inducing the expression of ATG12. Inhibition of autophagy via 3-MA or transfection of the siRNA targeting ATG12 can impair the antiaging effect of Rg1. Taken together, our data implicates that Rg1 can protect pulmonary epithelial cells from PQ-induced cellular senescence in an ATG12 dependent manner, which may provide a preventive and therapeutic strategy for PQ poisoning-induced pulmonary fibrosis.

Keywords:  autophagy; ginsenoside Rg1; paraquat; pulmonary fibrosis; senescence-associated secretory phenotype

DOI:  https://doi.org/10.1002/tox.23597
Biochem Biophys Rep. 2022 Jul;30 101281

Role of MicroRNAs in acceleration of vascular endothelial senescence.

Kensuke Toyama, Joshua M Spin, Alicia C Deng, Yasunori Abe, Philip S Tsao, Masaki Mogi.

  Backgrounds: Many factors are involved in cellular aging, and senescence induction requires complex regulation of various signaling networks and processes. Specifically, in the area of aging-related vascular cognitive impairment, laboratory-based findings have not yet yielded agents of practical use for clinical settings. One possible reason is that the physiologic elements of aging have been insufficiently considered. We sought to establish techniques to better model cellular aging using modulation of microRNAs, aiming to identify key microRNAs capable of fine-tuning aging-associated genes, and thereby regulating the senescence of vascular endothelial cells.Methods: We utilized expression microRNA arrays to evaluate control and senescent vascular endothelial cells in order to identify testable candidates. Bioinformatic analysis was used to select key microRNAs. These candidates were then modulated in vitro using microRNA mimics and inhibitors in endothelial cells, and senescence-associated gene expression patterns were evaluated by qPCR.
Results: Seventeen microRNAs were found to be significantly increased more than 2-fold in senescent cells. Of those, bioinformatic analysis concluded that miR-181a-5p, miR-30a-5p, miR-30a-3p, miR-100-5p, miR-21-5p, and miR-382-5p were likely associated with regulation of cellular senescence. We evaluated the potential targets of these six microRNAs by comparing them with cell-cycling and apoptosis-related genes from published mRNA transcriptional array data from aged tissues, and found that miR-181a-5p, miR-30a-5p and miR-30a-3p were enriched in overlapping targets compared with the other candidates. Modulation of these microRNAs in vascular endothelial cells revealed that over-expression of miR-30a-5p, and inhibition of both miR-30a-3p and miR-181a-5p, induced senescence.
Conclusion: miR-181a-5p, miR-30a-5p and miR-30a-3p likely contribute to aging-associated vascular endothelial cell senescence.

Keywords:  Cellular senescence; Vascular endothelial cells; microRNA

DOI:  https://doi.org/10.1016/j.bbrep.2022.101281
Aging Dis. 2022 Jun;13(3): 852-867

Stem Cell-derived Exosomal MicroRNA as Therapy for Vascular Age-related Diseases.

Hang Ren, Ziyuan Guo, Yang Liu, Chunli Song.

  Vascular age-related diseases describe a group of age-related chronic diseases that result in a considerable healthcare burden to society. Vascular aging includes structural changes and dysfunctions of endothelial cells (ECs) and smooth muscle cells (SMCs) in blood vessels. Compared with conventional treatment for vascular age-related diseases, stem cell (SC) therapy elicits better anti-aging effects viathe inhibition/delay ECs and SMCs from entering senescence. Exosomal noncoding RNA (ncRNAs) in vascular aging and stem cell-derived exosomal microRNAs (SCEV-miRNAs), especially in mesenchymal stem cells, have an important role in the development of age-related diseases. This review summarizes SCEV-miRNAs of diverse origins that may play a vital role in treating subclinical and clinical stages of vascular age-related disorders. We further explored possible age-related pathways and molecular targets of SCEV-miRNA, which are associated with dysfunctions of ECs and SMCs in the senescent stage. Moreover, the perspectives and difficulties of SCEV-miRNA clinical translation are discussed. This review aims to provide greater understanding of the biology of vascular aging and to identify critical therapeutic targets for SCEV-miRNAs. Though still in its infancy, the potential value of SCEV-miRNAs for vascular age-related diseases is clear.

Keywords:  MicroRNAs; senescence; stem cell-derived exosomal microRNA; vascular age-related diseases

DOI:  https://doi.org/10.14336/AD.2021.1110
Pharmazie. 2022 May 01. 77(5): 132-136

Selective Growth Suppressive Effect of Pravastatin on Senescent Human Lung Fibroblasts.

H Ushijima, A Onodera.

Various chemical reagents containing inhibitors of mitochondrial activity, antioxidants, nuclear factor-kappa B (NF-kB) inhibitor, mammalian target of rapamycin (mTOR) inhibitor and other clinical therapeutics were screened in order to identify those that selectively decrease the viability of senescent human lung fibroblasts. Cell viability was measured using the CCK-8 assay. The results showed that pravastatin, a drug for hyperlipidemia, decreased the viability of senescent cells but not non-senescent cells. The effect of pravastatin on senescent cells is thought to be due to the inhibition of cell proliferation, rather than cell death. The effect of pravastatin was further investigated using the glucose metabolism assay, which showed that glucose consumption was inhibited both in non-senescent and senescent cells and intracellular nicotinamide adenine dinucleotide (NAD) was decreased in senescent cells. Changes to the mRNA expression levels of senescence-associated genes in response to pravastatin treatment were quantified by real-time-qPCR. There were no significant changes in the relative mRNA expression levels of IL-1β, p16, p21, and p53 in pravastatin-treated non-senescent cells, whereas the expression of IL-1β and p16 were increased by pravastatin only in senescent cells. The results of this study suggest that pravastatin does not induce senolysis, but rather selectively inhibits the proliferation of senescent cells and that cellular senescence is enhanced by decreasing intracellular NAD and promoting IL-1β production.

DOI: https://doi.org/10.1691/ph.2022.2327
Redox Biol. 2022 May 27. pii: S2213-2317(22)00124-0. [Epub ahead of print]53 102352

Hyperbaric oxygen therapy for healthy aging: From mechanisms to therapeutics.

Qiaoyu Fu, Ran Duan, Yu Sun, Qingfeng Li.

  Hyperbaric oxygen therapy (HBOT), a technique through which 100% oxygen is provided at a pressure higher than 1 atm absolute (ATA), has become a well-established treatment modality for multiple conditions. The noninvasive nature, favorable safety profile, and common clinical application of HBOT make it a competitive candidate for several new indications, one of them being aging and age-related diseases. In fact, despite the conventional wisdom that excessive oxygen accelerates aging, appropriate HBOT protocols without exceeding the toxicity threshold have shown great promise in therapies against aging. For one thing, an extensive body of basic research has expanded our mechanistic understanding of HBOT. Interestingly, the therapeutic targets of HBOT overlap considerably with those of aging and age-related diseases. For another, pre-clinical and small-scale clinical investigations have provided validated information on the efficacy of HBOT against aging from various aspects. However, a generally applicable protocol for HBOT to be utilized in therapies against aging needs to be defined as a subsequent step. It is high time to look back and summarize the recent advances concerning biological mechanisms and therapeutic implications of HBOT in promoting healthy aging and shed light on prospective directions. Here we provide the first comprehensive overview of HBOT in the field of aging and geriatric research, which allows the scientific community to be aware of the emerging tendency and move beyond conventional wisdom to scientific findings of translational value.

Keywords:  Age-related disease; Aging intervention; Cellular senescence; Hyperbaric oxygen therapy; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2022.102352
J Lipid Atheroscler. 2022 May;11(2): 111-132

NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities.

Mahmoud Abdellatif, Heiko Bugger, Guido Kroemer, Simon Sedej.

  Nicotinamide adenine dinucleotide (NAD+) is an essential and pleiotropic coenzyme involved not only in cellular energy metabolism, but also in cell signaling, epigenetic regulation, and post-translational protein modifications. Vascular disease risk factors are associated with aberrant NAD+ metabolism. Conversely, the therapeutic increase of NAD+ levels through the administration of NAD+ precursors or inhibitors of NAD+-consuming enzymes reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular pathologies. As such, NAD+ has emerged as a potential target for combatting age-related cardiovascular and cerebrovascular disorders. This review discusses NAD+-regulated mechanisms critical for vascular health and summarizes new advances in NAD+ research directly related to vascular aging and disease, including hypertension, atherosclerosis, coronary artery disease, and aortic aneurysms. Finally, we enumerate challenges and opportunities for NAD+ repletion therapy while anticipating the future of this exciting research field, which will have a major impact on vascular medicine.

Keywords:  Aging; Autophagy; Hypertension; Inflammation; Mitochondria; Nicotinamide adenine dinucleotide; Vascular disease

DOI:  https://doi.org/10.12997/jla.2022.11.2.111
Aging Cell. 2022 Jun 03. e13648

Lifelong cytomegalovirus and early-LIFE irradiation synergistically potentiate age-related defects in response to vaccination and infection.

Jason L Pugh, Christopher P Coplen, Alona S Sukhina, Jennifer L Uhrlaub, Jose Padilla-Torres, Tomonori Hayashi, Janko Nikolich-Žugich.

  While whole-body irradiation (WBI) can induce some hallmarks of immune aging, (re)activation of persistent microbial infection also occurs following WBI and may contribute to immune effects of WBI over the lifespan. To test this hypothesis in a model relevant to human immune aging, we examined separate and joint effects of lifelong latent murine cytomegalovirus (MCMV) and of early-life WBI over the course of the lifespan. In late life, we then measured the response to a West Nile virus (WNV) live attenuated vaccine, and lethal WNV challenge subsequent to vaccination. We recently published that a single dose of non-lethal WBI in youth, on its own, was not sufficient to accelerate aging of the murine immune system, despite widespread DNA damage and repopulation stress in hematopoietic cells. However, 4Gy sub-lethal WBI caused manifest reactivation of MCMV. Following vaccination and challenge with WNV in the old age, MCMV-infected animals experiencing 4Gy, but not lower, dose of sub-lethal WBI in youth had reduced survival. By contrast, old irradiated mice lacking MCMV and MCMV-infected, but not irradiated, mice were both protected to the same high level as the old non-irradiated, uninfected controls. Analysis of the quality and quantity of anti-WNV immunity showed that higher mortality in MCMV-positive WBI mice correlated with increased levels of MCMV-specific immune activation during WNV challenge. Moreover, we demonstrate that infection, including that by WNV, led to MCMV reactivation. Our data suggest that MCMV reactivation may be an important determinant of increased late-life mortality following early-life irradiation and late-life acute infection.

Keywords:  DNA damage; T cells; West Nile virus; aging; cytomegalovirus; vaccination

DOI:  https://doi.org/10.1111/acel.13648
Front Bioeng Biotechnol. 2022 ;10 870324

Inflammatory Microenvironment Accelerates Bone Marrow Mesenchymal Stem Cell Aging.

Xin Peng, Xin Zhou, Ying Yin, Beibei Luo, Yang Liu, Cheng Yang.

  MSC senescence is considered a contributing factor in aging-related diseases. We investigated the influence of the inflammatory microenvironment on bone marrow mesenchymal stem cells (BMSCs) under aging conditions and the underlying mechanism to provide new ideas for stem cell therapy for age-related osteoporosis. The BMSCs were cultured until passage 3 (P3) (young group) and passage 10 (P10) (aging group) in vitro. The supernatant was collected as the conditioned medium (CM). The young BMSCs were cultured in the CM of P3 or P10 cells. The effects of CM from different groups on the aging and stemness of the young BMSCs were examined. A Quantibody® mouse inflammation array on serum extracts from young (aged 8 weeks) and old (aged 78 weeks) mice was performed, and differentially expressed factors were screened out. We discovered that the CM from senescent MSCs changed the physiology of young BMSCs. Systemic inflammatory microenvironments changed with age in the mice. In particular, the pro-inflammatory cytokine IL-6 increased, and the anti-inflammatory cytokine IL-10 decreased. The underlying mechanism was investigated by GO and KEGG analyses, and there was a change in the JAK-STAT signaling pathway, which is closely related to IL-6 and IL-10. Collectively, our results demonstrated that the age-related inflammatory microenvironment has a significant effect on the biological functions of BMSCs. Targeted reversal of this inflammatory environment may provide a new strategy for stem cell therapy to treat aging-related skeletal diseases.

Keywords:  aging; aging-related skeletal diseases; bone marrow mesenchymal stem cell; inflammatory microenvironment; stem cell therapy

DOI:  https://doi.org/10.3389/fbioe.2022.870324
Biochem Pharmacol. 2022 May 25. pii: S0006-2952(22)00201-5. [Epub ahead of print] 115107

Acid-sensitive ion channel 1a mediates osteoarthritis chondrocyte senescence by promoting Lamin B1 degradation.

Jie Ding, Yong Chen, Ying-Jie Zhao, Fan Chen, Lei Dong, Hai-Lin Zhang, Wei-Rong Hu, Shu-Fang Li, Ren-Peng Zhou, Wei Hu.

  Osteoarthritis (OA) is a common and debilitating chronic joint disease, which is characterized by degeneration of articular cartilage and the aging of chondrocytes. Acid-sensitive ion channel 1a (ASIC1a) is a proton-activated cationic channel abundant in chondrocytes, which senses and regulates joint cavity pH. Our previous study demonstrated that ASIC1a was involved in acid-induced rat articular chondrocyte senescence, but the mechanistic basis remained unclear. In this study, we explored the mechanism of ASIC1a in chondrocyte senescence and OA. The results showed that senescence-related-β-galactosidase, senescence-related markers (p53 and p21) and the autophagy-related protein Beclin-1 were found to be increased, but Lamin B1 was found to be reduced with acid (pH 6.0) treatment. These effects were inhibited by ASIC1a-specific blocker psalmotoxin-1 or ASIC1a-short hairpin RNA respectively in chondrocytes. Moreover, Silencing of Lamin B1 enhanced ASIC1a-mediated chondrocyte senescence, this effect was reversed by overexpression of Lamin B1, indicating that Lamin B1 was involved in ASIC1a-mediated chondrocyte senescence. Further, blockade of ASIC1a inhibits acid-induced autophagosomes and Beclin-1 protein expression, suggesting that ASIC1a is involved in acid-induced chondrocyte autophagy. Blocking autophagy with chloroquine inhibited Beclin-1 and increased Lamin B1 in acid-induced chondrocyte senescence. We further demonstrated that ASIC1a-mediated reduction of Lamin B1 expression was caused by autophagy pathway-dependent protein degradation. Finally, blocking ASIC1a protected cartilage tissue, restored Lamin B1 levels and inhibited chondrocyte senescence in a rat OA model. In summary, these findings suggest that ASIC1a may promote Lamin B1 degradation to mediate osteoarthritis chondrocyte senescence through the autophagy pathway.

Keywords:  ASIC1a; Acid; Autophagy; Lamin B1; Osteoarthritis; Senescence

DOI:  https://doi.org/10.1016/j.bcp.2022.115107
Hum Mol Genet. 2022 May 28. pii: ddac126. [Epub ahead of print]

Genotype-Phenotype Correlation of T Cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer's Disease.

Dallin Dressman, Thomas Buttrick, Maria Cimpean, David Bennett, Vilas Menon, Elizabeth M Bradshaw, Badri Vardarajan, Wassim Elyaman.

Recent studies identifying expression quantitative trait loci (eQTL) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells, and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer's disease (AD). We have performed RNA sequencing on four T cell subsets in genome-wide genotyped and well-characterized AD subjects and age- and sex-matched controls from the Religious Orders Study/Memory and Aging Project. We correlated gene expression data with AD neuropathological traits, and with single nucleotide polymorphisms (SNPs) to detect eQTLs. We identified several significant genes involved in T cell senescence and cytotoxicity, consistent with T cell RNA sequencing studies in aged/AD cohorts. We identified unexpected eQTLs previously associated with neuropsychiatric disease traits. Finally, we discovered that pathways related to axon guidance and synaptic function were enriched among trans-eQTLs in coding regions of the genome. Our data strengthen the potential link between T cell senescence and age-related neurodegenerative disease. In addition, our eQTL data suggest that T cell phenotypes may influence neuropsychiatric disorders, and can be influenced by genes involved in neurodevelopmental processes.

DOI: https://doi.org/10.1093/hmg/ddac126
Front Immunol. 2022 ;13 833531

Co-Expression of TIGIT and Helios Marks Immunosenescent CD8+ T Cells During Aging.

Daan K J Pieren, Noortje A M Smits, Rimke J Postel, Vinitha Kandiah, Jelle de Wit, Josine van Beek, Debbie van Baarle, Teun Guichelaar.

  Aging leads to alterations in the immune system that result in ineffective responsiveness against pathogens. Features of this process, collectively known as immunosenescence, accumulate in CD8+ T cells with age and have been ascribed to differentiation of these cells during the course of life. Here we aimed to identify novel markers in CD8+ T cells associated with immunosenescence. Furthermore, we assessed how these markers relate to the aging-related accumulation of highly differentiated CD27-CD28- cells. We found that co-expression of the transcription factor Helios and the aging-related marker TIGIT identifies CD8+ T cells that fail to proliferate and show impaired induction of activation markers CD69 and CD25 in response to stimulation in vitro. Despite this, in blood of older adults we found TIGIT+Helios+ T cells to become highly activated during an influenza-A virus infection, but these higher frequencies of activated TIGIT+Helios+ T cells associate with longer duration of coughing. Moreover, in healthy individuals, we found that TIGIT+Helios+ CD8+ T cells accumulate with age in the highly differentiated CD27-CD28- population. Interestingly, TIGIT+Helios+ CD8+ T cells also accumulate with age among the less differentiated CD27+CD28- T cells before their transit into the highly differentiated CD27-CD28- stage. This finding suggests that T cells with immunosenescent features become prominent at old age also within the earlier differentiation states of these cells. Our findings show that co-expression of TIGIT and Helios refines the definition of immunosenescent CD8+ T cells and challenge the current dogma of late differentiation stage as proxy for T-cell immunosenescence.

Keywords:  CD27; CD28; CD8+ T cells; Helios; TIGIT; aging; immunosenescence; influenza

DOI:  https://doi.org/10.3389/fimmu.2022.833531
Ageing Res Rev. 2022 May 26. pii: S1568-1637(22)00095-2. [Epub ahead of print] 101653

The Hallmarks of Aging in Ataxia-Telangiectasia.

Julio Aguado, Cecilia Gómez-Inclán, Hannah C Leeson, Martin F Lavin, Yosef Shiloh, Ernst J Wolvetang.

  Ataxia-telangiectasia (A-T) is caused by absence of the catalytic activity of ATM, a protein kinase that plays a central role in the DNA damage response, many branches of cellular metabolism, redox and mitochondrial homeostasis, and cell cycle regulation. A-T is a complex disorder characterized mainly by progressive cerebellar degeneration, immunodeficiency, radiation sensitivity, genome instability, and predisposition to cancer. It is increasingly recognized that the premature aging component of A-T is an important driver of this disease, and A-T is therefore an attractive model to study the aging process. This review outlines the current state of knowledge pertaining to the molecular and cellular signatures of aging in A-T and proposes how these new insights can guide novel therapeutic approaches for A-T.

Keywords:  ATM; Aging; Ataxia-telangiectasia; Cellular senescence; DNA damage response; Mitochondrial dysfunction; Oxidative stress

DOI:  https://doi.org/10.1016/j.arr.2022.101653
J Genet Genomics. 2022 May 30. pii: S1673-8527(22)00157-6. [Epub ahead of print]

Fecal microbiota transplantation from young donor mice improves ovarian function in aged mice.

Li Xu, Qiankun Zhang, Xiaowei Dou, Yipeng Wang, Jianwei Wang, Yong Zhou, Xingyin Liu, Jing Li.

  Advanced maternal age is characterized by declines in the quantity and quality of oocytes in the ovaries, and the aging process is accompanied by changes in gut microbiota composition. However, little is known about the relationship between gut microbiota and ovarian aging. By using fecal microbiota transplantation (FMT) to transplant material from young (5-week-old) into aged (42-week-old) mice, we find that the composition of gut microbiota in FMT-treated mice presents a "younger-like phenotype" and an increase of commensal bacteria, such as Bifidobacterium and Ruminococcaceae. Moreover, the FMT-treated mice show increased anti-inflammatory cytokine IL-4 and decreased pro-inflammatory cytokine IFN-γ. Fertility tests for assessing ovarian function reveal that the first litter size of female FMT-treated mice is significantly higher than that of the non-FMT group. Morphology analysis demonstrates a dramatic decrease in follicle atresia and apoptosis as well as an increase in cellular proliferation in the ovaries of the FMT-treated mice. Our results also show that FMT improves the immune microenvironment in aged ovaries, with decreased macrophages and macrophage-derived multinucleated giant cells (MNGCs). These results suggest that FMT from young donors could be a good choice for delaying ovarian aging.

Keywords:  gut microbiota; inflammatory cytokines; ovarian aging; ovarian microenvironment

DOI:  https://doi.org/10.1016/j.jgg.2022.05.006