bims-senagi 2021-05-23 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–05–23
27 papers selected by
Maria Grazia Vizioli, Mayo Clinic

Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology.
Senescence-associated β-galactosidase reveals the abundance of senescent CD8+ T cells in aging humans.
Age-related telomere attrition causes aberrant gene expression in sub-telomeric regions.
Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials.
Donor and Recipient Age-Mismatches: The Potential of Transferring Senescence.
The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis.
The nuclear sirtuin SIRT6 protects the heart from developing aging-associated myocyte senescence and cardiac hypertrophy.
Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair.
High-fat diet and dyslipidemia synergistically contribute to T cell senescence in gut associated lymphoid tissue.
Cytosolic dsDNA is a novel senescence marker associated with pyroptosis activation.
Methods to Study Myc-Regulated Cellular Senescence: An Update.
Emerging functions of circular RNA in aging.
Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.
RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness.
New insights into molecular changes in skeletal muscle aging and disease: Differential alternative splicing and senescence.
Senescent mesenchymal stem cells remodel extracellular matrix driving breast cancer cells to more invasive phenotype.
Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway.
The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration.
Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells.
[Mitochondrial DNA and cGAS-STING Innate Immune Signaling Pathway: Latest Research Progress].
FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway.
The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging.
STING Attenuates ROS Induced intervertebral disc degeneration.
Analysis of aging-related protein interactome and cross-network module comparisons across tissues provide new insights into aging.
Effects of exercise on cellular and tissue aging.
Immunosenescence and its influence on reproduction in a long-lived vertebrate.
Long-term tobacco exposure and immunosenescence: paradoxical effects on T-cells telomere length and telomerase activity.

Sci Adv. 2021 May;pii: eabe4601. [Epub ahead of print]7(21):

Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology.

Sandro Da Mesquita, Jasmin Herz, Morgan Wall, Taitea Dykstra, Kalil Alves de Lima, Geoffrey T Norris, Nisha Dabhi, Tatiana Kennedy, Wendy Baker, Jonathan Kipnis.

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)-dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer's disease-like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

DOI: https://doi.org/10.1126/sciadv.abe4601
Aging Cell. 2021 May;20(5): e13344

Senescence-associated β-galactosidase reveals the abundance of senescent CD8+ T cells in aging humans.

Ricardo I Martínez-Zamudio, Hannah K Dewald, Themistoklis Vasilopoulos, Lisa Gittens-Williams, Patricia Fitzgerald-Bocarsly, Utz Herbig.

  Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified. Using a second-generation fluorogenic substrate for β-galactosidase and multi-parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence-associated β-galactosidase (SA-βGal) activity with advancing donor age. The greatest age-associated increases were observed in CD8+ T-cell populations, in which the fraction of cells with high SA-βGal activity reached average levels of 64% in donors in their 60s. CD8+ T cells with high SA-βGal activity, but not those with low SA-βGal activity, were found to exhibit features of telomere dysfunction-induced senescence and p16-mediated senescence, were impaired in their ability to proliferate, developed in various T-cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts. Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age.

Keywords:  PBMC; T cells; aging; cellular senescence; immunosenescence; lymphocytes; p16; senescence-associated β-galactosidase; telomere

DOI:  https://doi.org/10.1111/acel.13344
Aging Cell. 2021 May 21. e13357

Age-related telomere attrition causes aberrant gene expression in sub-telomeric regions.

Xiao Dong, Shixiang Sun, Lei Zhang, Seungsoo Kim, Zhidong Tu, Cristina Montagna, Alexander Y Maslov, Yousin Suh, Tao Wang, Judith Campisi, Jan Vijg.

  Telomere attrition has been proposed as a biomarker and causal factor in aging. In addition to causing cellular senescence and apoptosis, telomere shortening has been found to affect gene expression in subtelomeric regions. Here, we analyzed the distribution of age-related differentially expressed genes from the GTEx RNA sequencing database of 54 tissue types from 979 human subjects and found significantly more upregulated than downregulated genes in subtelomeric regions as compared to the genome-wide average. Our data demonstrate spatial relationships between telomeres and gene expression in aging.

Keywords:  aging; gene expression; telomere shortening

DOI:  https://doi.org/10.1111/acel.13357
Front Pharmacol. 2021 ;12 630419

Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials.

Rossana Franzin, Alessandra Stasi, Elena Ranieri, Giuseppe Stefano Netti, Vincenzo Cantaluppi, Loreto Gesualdo, Giovanni Stallone, Giuseppe Castellano.

  The biological process of renal aging is characterized by progressive structural and functional deterioration of the kidney leading to end-stage renal disease, requiring renal replacement therapy. Since the discovery of pivotal mechanisms of senescence such as cell cycle arrest, apoptosis inhibition, and the development of a senescence-associated secretory phenotype (SASP), efforts in the understanding of how senescent cells participate in renal physiological and pathological aging have grown exponentially. This has been encouraged by both preclinical studies in animal models with senescent cell clearance or genetic depletion as well as due to evidence coming from the clinical oncologic experience. This review considers the molecular mechanism and pathways that trigger premature renal aging from mitochondrial dysfunction, epigenetic modifications to autophagy, DNA damage repair (DDR), and the involvement of extracellular vesicles. We also discuss the different pharmaceutical approaches to selectively target senescent cells (namely, senolytics) or the development of systemic SASP (called senomorphics) in basic models of CKD and clinical trials. Finally, an overview will be provided on the potential opportunities for their use in renal transplantation during ex vivo machine perfusion to improve the quality of the graft.

Keywords:  DNA damage repair; extracellular vesicles; metformin; mitochondrial dysfunction; rapamycin; renal ageing; senescence; senolytics

DOI:  https://doi.org/10.3389/fphar.2021.630419
Front Immunol. 2021 ;12 671479

Donor and Recipient Age-Mismatches: The Potential of Transferring Senescence.

Jasper Iske, Tomohisa Matsunaga, Hao Zhou, Stefan G Tullius.

  In transplantation, donor and recipients frequently differ in age. Senescent cells accumulate in donor organs with aging and have the potential to promote senescence in adjacent cells when transferred into recipient animals. Characteristically, senescent cells secrete a myriad of pro-inflammatory, soluble molecules as part of their distinct secretory phenotype that have been shown to drive senescence and age-related co-morbidities. Preliminary own data show that the transplantation of old organs limits the physical reserve of recipient animals. Here, we review how organ age may affect transplant recipients and discuss the potential of accelerated aging.

Keywords:  immune aging; immunosenescence; immunosenescence and inflammaging; passenger leukocytes; senescent associated secretory phenotype; senescent cell

DOI:  https://doi.org/10.3389/fimmu.2021.671479
Tissue Eng Regen Med. 2021 May 18.

The Senolytic Drug JQ1 Removes Senescent Cells via Ferroptosis.

Seokhyeong Go, Mikyung Kang, Sung Pil Kwon, Mungyo Jung, Ok Hee Jeon, Byung-Soo Kim.

   BACKGROUND: Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis.
METHODS: Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining.
RESULTS: At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells.
CONCLUSION: The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.

Keywords:  Cellular senescence; Ferroptosis; JQ1; Senolytic drug

DOI:  https://doi.org/10.1007/s13770-021-00346-z
Aging (Albany NY). 2021 May 02. 13(9): 12334-12358

The nuclear sirtuin SIRT6 protects the heart from developing aging-associated myocyte senescence and cardiac hypertrophy.

Vinodkumar B Pillai, Sadhana Samant, Samantha Hund, Madhu Gupta, Mahesh P Gupta.

  Sirtuins have been shown to regulate the aging process. We have previously demonstrated that Sirt6 blocks the pressure overload-induced cardiac hypertrophy in mice. Here, we show that Sirt6 can also mitigate aging-induced cardiomyocyte senescence and cardiac hypertrophy. We found that aging is associated with altered Sirt6 activity along with development of cardiac hypertrophy and fibrosis. Compared to young mice (4-months), the hearts of aged mice (24-months) showed increased levels of mitochondrial DNA damage, shortened telomere length, and increased accumulation of 8-oxo-dG adducts, which are hallmarks of aging. The aged hearts also showed reduced levels of NAD+ and altered levels of mitochondrial fusion-fission proteins. Similar characteristics were observed in the hearts of Sirt6 deficient mice. Additionally, we found that doxorubicin (Dox) induced cardiomyocyte senescence, as measured by expression of p16INK4a, p53, and β-galactosidase, was associated with loss of Sirt6. However, Sirt6 overexpression protected cardiomyocytes from developing Dox-induced senescence. Further, compared to wild-type mice, the hearts of Sirt6.Tg mice showed reduced expression of aging markers, and the development of aging-associated cardiac hypertrophy and fibrosis. Our data suggest that Sirt6 is a critical anti-aging molecule that regulates various cellular processes associated with aging and protects the heart from developing aging-induced cardiac hypertrophy and fibrosis.

Keywords:  Sirt6; cardiac aging

DOI:  https://doi.org/10.18632/aging.203027
Sci Transl Med. 2021 May 19. pii: eabb0203. [Epub ahead of print]13(594):

Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair.

Katie J Mylonas, Eoin D O'Sullivan, Duncan Humphries, David P Baird, Marie-Helena Docherty, Sarah A Neely, Paul J Krimpenfort, Anette Melk, Roland Schmitt, Sofia Ferreira-Gonzalez, Stuart J Forbes, Jeremy Hughes, David A Ferenbach.

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor β1, induced fibrosis, and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B cell lymphoma 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.

DOI: https://doi.org/10.1126/scitranslmed.abb0203
Exp Gerontol. 2021 May 18. pii: S0531-5565(21)00186-8. [Epub ahead of print] 111404

High-fat diet and dyslipidemia synergistically contribute to T cell senescence in gut associated lymphoid tissue.

Yuchen Li, Xia Li, Qian Xue, Jingtong Wang, Jiang Tan.

  Obesity can compromise immune response and immune surveillance. Recent studies have linked obesity with systemic T cell senescence and thymus involution. However, these studies failed to distinguish the influence of obesity from the influence of diet composition on premature T cell senescence. High-fat diet (HFD) can influence the immunity of gut-associated lymphoid tissue (GALT) preceding the onset of obesity. Despite GALT is sensitive to the changes in the dietary composition and metabolic status, it still remains elusive how HFD and obesity contribute to T cell senescence in the GALT. In this study, we illustrated the interplay of the HFD, obesity and intestinal immunity by comparing the immune features of diet-induced obese (DIO) to those of diet-resistant (DR) mice. As expected, DIO mice exhibited increased serum lipid levels and liver steatosis whereas dyslipidemia was absent in DR mice. DIO mice demonstrated a shift from naïve to effector-memory (EM) phenotype in the T cells derived from the spleens and PPs. Moreover, DIO mice showed up-regulation of PD1 and KLRG1 on the T cells. Similar but mild trends were observed in the naïve and EM T cells from DR mice. Furthermore, we proved that senescent-like changes in splenic and PPs-derived T cells positively correlated with the serum lipid concentrations. Taken together, our results indicate that HFD components function synergistically with dyslipidemia to induce T cell senescence in the GALT.

Keywords:  Gut-associated lymphoid tissue; High-fat diet; Intestinal immunity; Obesity; T cell senescence

DOI:  https://doi.org/10.1016/j.exger.2021.111404
Tissue Cell. 2021 Apr 30. pii: S0040-8166(21)00070-7. [Epub ahead of print]72 101554

Cytosolic dsDNA is a novel senescence marker associated with pyroptosis activation.

Ruoyu Zhou, Xiaoli Xie, Ziyi Qin, Xinbo Li, Jing Liu, Haili Li, Quan Zheng, Ying Luo.

  Cellular senescence has become a research focus because of its dual roles in ageing and tumorigenesis. The biomarkers of senescence are essential for detecting senescent cells and understanding the ageing process and its regulation. Here, we identify cytosolic double-stranded DNA (dsDNA) as a novel sensitive biomarker for cellular senescence of mouse embryonic fibroblasts (MEFs) in response to common types of stimuli, including replicative stress, genetic modification and oxidative stress. We found that the accumulation of cytosolic dsDNA was positively correlated with the senescence process in MEFs and was detectable earlier than senescence-associated β-galactosidase (SA-β-Gal) staining, which is the current gold standard for senescence detection. Due to the immunogenicity of dsDNA, we further investigated the stimulation of two dsDNA sensors, cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) and absent in melanoma-2 (AIM2). The results showed that the cGAS protein level did not significantly change upon senescence stimulation, while AIM2 expression was significantly upregulated in senescent cells. Surprisingly, we found that ageing-related cytosolic dsDNA induced significant pyroptosis activation in the senescent MEFs. These data reveal novel easy-to-detect biomarker for cellular senescence. The activation of downstream immunological response pathways might add new experimental evidence for inflammatory ageing.

Keywords:  AIM2; Biomarker; Cellular senescence; Cytosolic dsDNA; cGAS

DOI:  https://doi.org/10.1016/j.tice.2021.101554
Methods Mol Biol. 2021 ;2318 241-254

Methods to Study Myc-Regulated Cellular Senescence: An Update.

Fan Zhang, Wesam Bazzar, Mohammad Alzrigat, Lars-Gunnar Larsson.

  Cellular senescence plays a role in several physiological processes including aging, embryonic development, tissue remodeling, and wound healing and is considered one of the main barriers against tumor development. Studies of normal and tumor cells both in culture and in vivo suggest that MYC plays an important role in regulating senescence, thereby contributing to tumor development. We have previously described different common methods to measure senescence in cell cultures and in tissues. Unfortunately, there is no unique marker that unambiguously defines a senescent state, and it is therefore necessary to combine measurements of several different markers in order to assure the correct identification of senescent cells. Here we describe protocols for simultaneous detection of multiple senescence markers in situ, a quantitative fluorogenic method to measure senescence-associated β-galactosidase activity (SA-β-gal), and a new method to detect senescent cells based on the Sudan Black B (SBB) analogue GL13, which is applicable to formalin-fixed paraffin-embedded tissues. The application of these methods in various systems will hopefully shed further light on the role of MYC in regulation of senescence, and how that impacts normal physiological processes as well as diseases and in particular cancer development.

Keywords:  Cellular senescence; EdU; MUG assay; MYC; Phalloidin; SA-β-gal; Sudan Black B GL13

DOI:  https://doi.org/10.1007/978-1-0716-1476-1_12
Trends Genet. 2021 May 17. pii: S0168-9525(21)00126-8. [Epub ahead of print]

Emerging functions of circular RNA in aging.

Eunah Kim, Yoon Ki Kim, Seung-Jae V Lee.

  Circular RNA (circRNA) is a closed, single-stranded transcript widely detected in eukaryotes. Recent studies indicate that the levels of circRNAs change with age in various tissues in multiple species, ranging from nematodes to mammals. Here we discuss the functional roles of circRNAs in animal aging and longevity. We review studies regarding the differential expression of circRNAs that contributes to cellular senescence and the pathogenesis of aging-associated diseases. We explore the features of aging-associated circRNAs by discussing their potential as biomarkers of aging, tissue specificity, physiological roles, action mechanisms, and evolutionarily conserved characteristics. Our review provides insights into current progress in circRNA research and their significant functions in the aging process.

Keywords:  age-associated disease; aging; biomarker of aging; circular RNAs; senescence

DOI:  https://doi.org/10.1016/j.tig.2021.04.014
Commun Biol. 2021 May 21. 4(1): 611

Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.

Anna K Uryga, Mandy O J Grootaert, Abel M Garrido, Sebnem Oc, Kirsty Foote, Joel Chappell, Alison Finigan, Francesca Rossiello, Fabrizio d'Adda di Fagagna, Dimitra Aravani, Helle F Jorgensen, Martin R Bennett.

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2T188A expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease.

DOI: https://doi.org/10.1038/s42003-021-02123-z
Dev Cell. 2021 May 11. pii: S1534-5807(21)00360-9. [Epub ahead of print]

RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness.

Sandra Benítez, Alex Cordero, Patricia G Santamaría, Jaime Redondo-Pedraza, Ana S Rocha, Alejandro Collado-Solé, Maria Jimenez, Adrian Sanz-Moreno, Guillermo Yoldi, Juliana C Santos, Ilaria De Benedictis, Clara Gómez-Aleza, Sabela Da Silva-Álvarez, Kevin Troulé, Gonzalo Gómez-López, Noelia Alcazar, Ignacio Palmero, Manuel Collado, Manuel Serrano, Eva Gonzalez-Suarez.

  Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.

Keywords:  breast cancer; mammary gland; metastasis; receptor activator of NFkB; senescence; senolytics; stemness

DOI:  https://doi.org/10.1016/j.devcel.2021.04.022
Mech Ageing Dev. 2021 May 18. pii: S0047-6374(21)00082-8. [Epub ahead of print] 111510

New insights into molecular changes in skeletal muscle aging and disease: Differential alternative splicing and senescence.

Elizaveta Solovyeva, Chikwendu Ibebunjo, Stephan Utzinger, John K Eash, Andrew Dunbar, Ulrike Naumann, Yunyu Zhang, Fabrizio C Serluca, Sabrina Demirci, Berndt Oberhauser, Frederique Black, Martin Rausch, Sebastian Hoersch, Angelika Meyer.

  Progressive loss of muscle mass and function due to muscle fiber atrophy and loss in the elderly and chronically ill is now defined as sarcopenia. It is a major contributor to loss of independence, disability, need of long-term care as well as overall mortality. Sarcopenia is a heterogenous disease and underlying mechanisms are not completely understood. Here, we newly identified and used Tmem158, alongside Cdkn1a, as relevant senescence and denervation markers (SDMs), associated with muscle fiber atrophy. Subsequent application of laser capture microdissection (LCM) and RNA analyses revealed age- and disease-associated differences in gene expression and alternative splicing patterns in a rodent sarcopenia model. Of note, genes exhibiting such differential alternative splicing (DAS) are mainly involved in the contractile function of the muscle. Many of these splicing events are also found in a mouse model for myotonic dystrophy type 1 (DM1), underscoring the premature aging phenotype of this disease. We propose to add differential alternative splicing to the hallmarks of aging.

Keywords:  Cellular senescence; Differential alternative splicing; Laser Capture Microdissection; Myotonic dystrophy type 1; Sarcopenia

DOI:  https://doi.org/10.1016/j.mad.2021.111510
J Cell Sci. 2020 Jan 01. pii: jcs.232470. [Epub ahead of print]

Senescent mesenchymal stem cells remodel extracellular matrix driving breast cancer cells to more invasive phenotype.

Deepraj Ghosh, Carolina Mejia-Pena, Nhat Quach, Botai Xuan, Amy H Lee, Michelle R Dawson.

  Mesenchymal stem cells accumulated in tissue specific sites are essential for the regenerative process; however, biological aging and environmental stress can induce senescence - an irreversible state of growth arrest - that not only affects the behavior of cells but also disrupts their ability to restore tissue integrity. While abnormal tissue properties including increased extracellular matrix stiffness are linked with the risk of developing breast cancer, the role and contribution of senescent MSCs to the disease progression to malignancy are not well understood. Here, we investigated senescence associated biophysical changes in MSCs and how they influence cancer cell behavior in a 3D matrix interface model. Although senescent MSCs were far less motile than pre-senescent MSCs, they induced an invasive breast cancer phenotype, characterized by increased spheroid growth and cell invasion in collagen gels. Further analysis of collagen gels using second harmonic generation showed increased collagen density when senescent MSCs were present, suggesting that senescent MSCs actively remodel the surrounding matrix. This study provides direct evidence of the pro-malignant effects of senescent MSCs in tumors.

Keywords:  Breast cancer; Cancer cell invasion; ECM remodeling; Mesenchymal stem cells; Senescence

DOI:  https://doi.org/10.1242/jcs.232470
Cell Commun Signal. 2021 May 20. 19(1): 58

Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway.

Lu Zhou, Yi-Fei Zhang, Fu-Hua Yang, Han-Qing Mao, Zhi Chen, Lu Zhang.

   BACKGROUND: Mitochondrial DNA (mtDNA) is a vital driver of inflammation when it leaks from damaged mitochondria into the cytosol. mtDNA stress may contribute to cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway activation in infectious diseases. Odontoblasts are the first cells challenged by cariogenic bacteria and involved in maintenance of the pulp immune and inflammatory responses to dentine-invading pathogens. In this study, we investigated that mtDNA as an important inflammatory driver participated in defending against bacterial invasion via cGAS-STING pathway in odontoblasts.
METHODS: The normal tissues, caries tissues and pulpitis tissues were measured by western blotting and immunohistochemical staining. Pulpitis model was built in vitro to evaluated the effect of the cGAS-STING pathway in odontoblast-like cell line (mDPC6T) under inflammation. Western blot and real-time PCR were performed to detect the expression of cGAS-STING pathway and pro-inflammatory cytokines. The mitochondrial function was evaluated reactive oxygen species (ROS) generated by mitochondria using MitoSOX Red dye staining. Cytosolic DNA was assessed by immunofluorescent staining and real-time PCR in mDPC6T cells after LPS stimulation. Furthermore, mDPC6T cells were treated with ethidium bromide (EtBr) to deplete mtDNA or transfected with isolated mtDNA. The expression of cGAS-STING pathway and pro-inflammatory cytokines were measured.
RESULTS: The high expression of cGAS and STING in caries and pulpitis tissues in patients, which was associated with inflammatory progression. The cGAS-STING pathway was activated in inflamed mDPC6T. STING knockdown inhibited the nuclear import of p65 and IRF3 and restricted the secretion of the inflammatory cytokines CXCL10 and IL-6 induced by LPS. LPS caused mitochondrial damage in mDPC6T, which promoted mtDNA leakage into the cytosol. Depletion of mtDNA inhibited the cGAS-STING pathway and nuclear translocation of p65 and IRF3. Moreover, repletion of mtDNA rescued the inflammatory response, which was inhibited by STING knockdown.
CONCLUSION: Our study systematically identified a novel mechanism of LPS-induced odontoblast inflammation, which involved mtDNA leakage from damaged mitochondria into the cytosol stimulating the cGAS-STING pathway and the inflammatory cytokines IL-6 and CXCL10 secretion. The mtDNA-cGAS-STING axis could be a potent therapeutic target to prevent severe bacterial inflammation in pulpitis. Video Abstract.

Keywords:  Immune response; Inflammation; Mitochondrial DNA; Mitochondrial damage; Odontoblasts; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s12964-021-00738-7
Front Aging Neurosci. 2021 ;13 638208

The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration.

Nicolás W Martinez, Felipe E Gómez, Soledad Matus.

  There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer's disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR's contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; aging; double-stranded RNA-dependent protein kinase; integrated stress response; neurocognitive functions

DOI:  https://doi.org/10.3389/fnagi.2021.638208
Stem Cell Reports. 2021 May 07. pii: S2213-6711(21)00211-3. [Epub ahead of print]

Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells.

Donna M Poscablo, Atesh K Worthington, Stephanie Smith-Berdan, E Camilla Forsberg.

  Age-related morbidity is associated with a decline in hematopoietic stem cell (HSC) function, but the mechanisms of HSC aging remain unclear. We performed heterochronic HSC transplants followed by quantitative analysis of cell reconstitution. Although young HSCs outperformed old HSCs in young recipients, young HSCs unexpectedly failed to outcompete the old HSCs of aged recipients. Interestingly, despite substantial enrichment of megakaryocyte progenitors (MkPs) in old mice in situ and reported platelet (Plt) priming with age, transplanted old HSCs were deficient in reconstitution of all lineages, including MkPs and Plts. We therefore performed functional analysis of young and old MkPs. Surprisingly, old MkPs displayed unmistakably greater regenerative capacity compared with young MkPs. Transcriptome analysis revealed putative molecular regulators of old MkP expansion. Collectively, these data demonstrated that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging.

Keywords:  age-related hematopoiesis; cell-extrinsic; cell-intrinsic; hematopoietic stem cell; heterochronic HSC transplants; megakaryocyte progenitors; platelets; quantitative reconstitution; regenerative capacity; transcriptome

DOI:  https://doi.org/10.1016/j.stemcr.2021.04.016
Sichuan Da Xue Xue Bao Yi Xue Ban. 2021 May;52(3): 387-395

[Mitochondrial DNA and cGAS-STING Innate Immune Signaling Pathway: Latest Research Progress].

Yong-Xing Li, Shu-Fang Cui, Wei Meng, Hai-Yang Hu, Chen Wang.

  Mitochondria are important organelles that present extensively in cells, serving diverse functions. In addition to controlling cell energy production and metabolism, mitochondria are also involved in various biological processes, including anti-infection, apoptosis, and autophagy. Harmful stimuli from external environment or those generated by the cells themselves can damage mitochondria and cause mitochondrial stress response, during which the mitochondrial matrix containing mitochondrial DNA (mtDNA) can leak into the cytoplasm. Cytoplasmic mtDNA, acting as a damage-associated molecular pattern (DAMP), can activate a panel of DNA sensors and elicit innate immune response in organisms. Cyclic GMP-AMP synthase (cGAS), a key intracellular DNA sensor, can catalyze the conversion of GTP and ATP to cyclic GMP-AMP (2'3'-cGAMP), which serves as second messenger to bind and activate stimulator of interferon gene (STING), an endoplasmic adaptor protein. Beyond its critical roles in anti-microbial immunity, cGAS-STING pathway also serves important functions in many pathological and physiological processes such as autoimmunity, tumor and senescence. In this review, we focus on how the mtDNA released during mitochonrial stress response activates the cGAS-STING innate immune signaling pathway and the associated diseases, in order to help promote basic research about the role of mitochondria in innate immunity and provide new strategies for developing mitochondria-targeting drugs.

Keywords:  Innate immunity; Mitochondrial DNA; Mitochondrial stress; STING; cGAS-STING signaling

DOI:  https://doi.org/10.12182/20210560501
Autophagy. 2021 May 19. 1-22

FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway.

Zu-Hong He, Ming Li, Qiao-Jun Fang, Fu-Ling Liao, Sheng-Yu Zou, Xia Wu, Hai-Ying Sun, Xue-Yan Zhao, Yu-Juan Hu, Xiao-Xiang Xu, Sen Chen, Yu Sun, Ren-Jie Chai, Wei-Jia Kong.

  Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.Abbreviations: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.

Keywords:  Aging-related hearing loss; FOXG1; ROS; autophagy; hair cell

DOI:  https://doi.org/10.1080/15548627.2021.1916194
Oxid Med Cell Longev. 2021 ;2021 6635460

The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging.

Chao Yu, Jian-Hui Xiao.

Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to the disruption of redox signals and causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence-related diseases and in aging itself. The Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) system can be used to monitor oxidative stress; Keap1-Nrf2 is closely associated with aging and controls the transcription of multiple antioxidant enzymes. Simultaneously, Keap1-Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen-activated protein kinase. This review presents more information on aging-related molecular mechanisms involving Keap1-Nrf2. Furthermore, we highlight several major signals involved in Nrf2 unbinding from Keap1, including cysteine modification of Keap1 and phosphorylation of Nrf2, PI3K/Akt/glycogen synthase kinase 3β, sequestosome 1, Bach1, and c-Myc. Additionally, we discuss the direct interaction between Keap1-Nrf2 and the mammalian target of rapamycin pathway. In summary, we focus on recent progress in research on the Keap1-Nrf2 system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs.

DOI: https://doi.org/10.1155/2021/6635460
Osteoarthritis Cartilage. 2021 May 18. pii: S1063-4584(21)00731-7. [Epub ahead of print]

STING Attenuates ROS Induced intervertebral disc degeneration.

Qiang Guo, Dingchao Zhu, Yihan Wang, Zhimin Miao, Zexin Chen, Zhen Lin, Jiahao Lin, Chongan Huang, Ligang Pan, Libo Wang, Shanshan Zeng, Jinwu Wang, Xiangtao Zheng, Yan Lin, Xiaolei Zhang, Yaosen Wu.

   OBJECTIVE: DNA damage induced by ROS is considered one of the main causes of nucleus pulposus (NP) cells degeneration during the progression of intervertebral disc degeneration (IVDD). cGAS-STING pathway acts as DNA-sensing mechanism for monitoring DNA damage. Recent studies have proved that cGAS-STING contributes to the development of various diseases by inducing inflammation, senescence, and apoptosis. This work explored the role of STING, the main effector of cGAS-STING signaling pathway, in NP degeneration.
METHOD: Immunohistochemistry was conducted to measure STING protein levels in the nucleus pulposus tissues from human and puncture-induced IVDD rat models. TBHP induces degeneration of nucleus pulposus cells in vitro. For in vivo experiments, lv-NC or lv-STING were injected into the central intervertebral disc space. The degeneration level of IVDD was assessed by MRI, X-ray, HE, and Safranin O staining.
RESULTS: We found that the expression of STING was upregulated in human and rat degenerated NP tissue as well as in TBHP-treated NP cells. Overexpression of STING promoted the degradation of extracellular matrix; it also promoted apoptosis and senescence of TBHP-treated and untreated NP cells. Knock-down of STING significantly reversed these effects. Mechanistically, STING activated IRF3, whereas blockage of IRF3 attenuated STING-induced apoptosis, senescence and ECM degradation. In vivo experiments revealed that STING knock-down alleviated puncture-induced IVDD development.
CONCLUSION: STING promotes IVDD progress via IRF3, while suppression of STING may be a promising treatment for IVDD.

Keywords:  Apoptosis; Intervertebral disc degeneration; Senescence; cGAS-STING

DOI:  https://doi.org/10.1016/j.joca.2021.04.017
Comput Biol Chem. 2021 May 07. pii: S1476-9271(21)00073-6. [Epub ahead of print]92 107506

Analysis of aging-related protein interactome and cross-network module comparisons across tissues provide new insights into aging.

Vinay Randhawa, Manoj Kumar.

  Delaying the human aging process and thus eliminating the risk factors for age-related diseases is one of the prime objectives. While various aging-associated genes and proteins have been characterized, which provide a significant understanding of the human aging process, a significant success in regulating aging is not achieved yet. Understanding how aging proteins interact with each other and also with other proteins could provide important insights into the underlying mechanisms governing the aging process. Therefore, in this work, information of gene expression was included to the static aging-related protein interactome to understand the network-based relationships among aging-related essential (AE) proteins, aging-related non-essential (ANE) proteins, and housekeeping-proteins that could regulate or influence aging. Comprehensive analyses provided various systems-level insights into the regulatory characteristics of aging; for example, (i) network-based correlation analysis predicted functional relationships among AE proteins and ANE proteins; (ii) network variability analysis predicted aging to affect different tissues in strikingly different ways by differentially regulating various regulatory interactions; (iii) cross-network comparisons identified two aging-related modules to be significantly conserved across most of the tissues. Overall, the findings obtained during this study could be helpful for researchers to delay, prevent, or even reverse various aspects of the aging.

Keywords:  Aging protein interactome; Cross-network comparison; Network correlation; Network variability

DOI:  https://doi.org/10.1016/j.compbiolchem.2021.107506
Aging (Albany NY). 2021 May 13. 13

Effects of exercise on cellular and tissue aging.

Priscila Viana Carapeto, Cristina Aguayo-Mazzucato.

  The natural aging process is carried out by a progressive loss of homeostasis leading to a functional decline in cells and tissues. The accumulation of these changes stem from a multifactorial process on which both external (environmental and social) and internal (genetic and biological) risk factors contribute to the development of adult chronic diseases, including type 2 diabetes mellitus (T2D). Strategies that can slow cellular aging include changes in diet, lifestyle and drugs that modulate intracellular signaling. Exercise is a promising lifestyle intervention that has shown antiaging effects by extending lifespan and healthspan through decreasing the nine hallmarks of aging and age-associated inflammation. Herein, we review the effects of exercise to attenuate aging from a clinical to a cellular level, listing its effects upon various tissues and systems as well as its capacity to reverse many of the hallmarks of aging. Additionally, we suggest AMPK as a central regulator of the cellular effects of exercise due to its integrative effects in different tissues. These concepts are especially relevant in the setting of T2D, where cellular aging is accelerated and exercise can counteract these effects through the reviewed antiaging mechanisms.

Keywords:  AMPK; aging; exercise; type 2 diabetes

DOI:  https://doi.org/10.18632/aging.203051
J Exp Biol. 2020 Jan 01. pii: jeb.223057. [Epub ahead of print]

Immunosenescence and its influence on reproduction in a long-lived vertebrate.

Jessica M Judson, Dawn M Reding, Anne M Bronikowski.

  Immunosenescence is a well-known phenomenon in mammal systems, but its relevance in other long-lived vertebrates is less understood. Further, the influence of age and reproductive effort on immune function in long-lived species can be challenging to assess, as long-term data are scarce and it is often difficult to sample the oldest age classes. We used the painted turtle (Chrysemys picta) to test hypotheses of immunosenescence and a trade-off between reproductive output and immune function in a population of a long-lived vertebrate that has been monitored for over 30 years. These long-term data are utilized to employ a unique approach of aging turtles with mark-recapture data and population-specific growth modeling to obtain more accurate estimates of age. We analyzed natural antibodies, lysis ability, and bactericidal competence in 126 individuals from 1 to 33 years of age captured during May and June in 2011. Older turtles exhibited greater natural antibody levels than young individuals across sexes. Young females with large clutches exhibited greater lysis ability, while older females with large clutches had decreased lysis ability, suggesting a trade-off between reproductive output and immune function conditional upon age. However, bactericidal competence increased later in the nesting season for older females. Our study rejects the hypothesis of immunosenescence in a long-lived turtle, despite evidence of actuarial and reproductive senescence in this population. Additionally, we detected mixed evidence for a trade-off between reproduction and immune health.

Keywords:  Immune function; Reptile; Senescence; Sex-specific

DOI:  https://doi.org/10.1242/jeb.223057
Mech Ageing Dev. 2021 May 14. pii: S0047-6374(21)00073-7. [Epub ahead of print] 111501

Long-term tobacco exposure and immunosenescence: paradoxical effects on T-cells telomere length and telomerase activity.

Juliana Ruiz Fernandes, Thalyta Nery Carvalho Pinto, Lucas Lopes Piemonte, Liã Barbara Arruda, Cibele Cristine Berto Marques da Silva, Celso Ricardo Fernandes de Carvalho, Regina Maria Carvalho Pinto, Alberto José da Silva Duarte, Gil Benard.

  Immunosenescence are alterations on immune system that occurs throughout an individual life. The main characteristic of this process is replicative senescence, evaluated by telomere shortening. Several factors implicate on telomere shortening, such as smoking. In this study, we evaluated the influence of smoking and Chronic Obstructive Pulmonary Disease (COPD) on cytokines, telomere length and telomerase activity. Blood samples were collected from subjects aged over 60 years old: Healthy (never smokers), Smokers (smoking for over 30 years) and COPDs (ex-smokers for ≥15 years). A young group was included as control. PBMCs were cultured for assessment of telomerase activity using RT-PCR, and cytokines secretion flow cytometry. CD4+ and CD8+ purified lymphocytes were used to assess telomere length using FlowFISH. We observed that COPD patients have accelerated telomere shortening. Paradoxically, smokers without lung damage showed preserved telomere length, suggesting that tobacco smoking may affect regulatory mechanisms, such as telomerase. Telomerase activity showed diminished activity in COPDs, while Smokers showed increased activity compared to COPDs and Healthy groups. Extracellular environment reflected this unbalance, indicated by an anti-inflammatory profile in Smokers, while COPDs showed an inflammatory prone profile. Further studies focusing on telomeric maintenance may unveil mechanisms that are associated with cancer under long-term smoking.

Keywords:  Immunosenescence; replicative senescence; telomere; tobacco exposure

DOI:  https://doi.org/10.1016/j.mad.2021.111501