bims-senagi 2021-06-13 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–06–13
thirty-one papers selected by
Maria Grazia Vizioli, Mayo Clinic

Senolytics alleviate the degenerative disorders of temporomandibular joint in old age.
Exercise reduces circulating biomarkers of cellular senescence in humans.
Senolytics reduce coronavirus-related mortality in old mice.
The role of T cells in age-related diseases.
Acid ceramidase promotes senescent cell survival.
Evaluating causality of cellular senescence in non-alcoholic fatty liver disease.
Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress.
Interferon regulatory factor 7 impairs cellular metabolism in aging adipose-derived stromal cells.
The Role of Rapamycin in Healthspan Extension via the Delay of Organ Aging.
STING inhibitors target the cyclic dinucleotide binding pocket.
Lipid accumulation-induced hepatocyte senescence regulates the activation of hepatic stellate cells through the Nrf2-antioxidant response element pathway.
Advanced maternal age causes premature placental senescence and malformation via dysregulated α-Klotho expression in trophoblasts.
Interphase Chromosomes in Replicative Senescence: Chromosome Positioning as a Senescence Biomarker and the Lack of Nuclear Motor-Driven Chromosome Repositioning in Senescent Cells.
Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death.
Histone Deacetylase 2 Suppresses Skeletal Muscle Atrophy and Senescence via NF-κB Signaling Pathway in Cigarette Smoke-Induced Mice with Emphysema.
Cell Stress during Development and Disease - Special Issue, Review article Balancing DNA repair to prevent ageing and cancer.
Mitochondria: Their relevance during oocyte ageing.
Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways.
Aneuploid senescent cells activate NF-κB to promote their immune clearance by NK cells.
Bacterial genotoxins induce T cell senescence.
Multiple Roles of IL-6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis.
Myofibroblast fate plasticity in tissue repair and fibrosis: de-activation, apoptosis, senescence and reprogramming.
Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution.
Age-related amyloidosis outside the brain: A state-of-the-art review.
Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology.
Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.
Are fat and sugar just as detrimental in old age?
Systemic transplantation of adult multipotent stem cells prevents articular cartilage degeneration in a mouse model of accelerated ageing.
Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice.
Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging.
G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence.

Aging Cell. 2021 Jun 08. e13394

Senolytics alleviate the degenerative disorders of temporomandibular joint in old age.

Yueying Zhou, Iman M A Al-Naggar, Po-Jung Chen, Nathan S Gasek, Ke Wang, Shivam Mehta, George A Kuchel, Sumit Yadav, Ming Xu.

  Aging is one of the major risk factors for degenerative joint disorders, including those involving the temporomandibular joint (TMJ). TMJ degeneration occurs primarily in the population over 65, significantly increasing the risk of joint discomfort, restricted joint mobility, and reduced quality of life. Unfortunately, there is currently no effective mechanism-based treatment available in the clinic to alleviate TMJ degeneration with aging. We now demonstrate that intermittent administration of senolytics, drugs which can selectively clear senescent cells, preserved mandibular condylar cartilage thickness, improved subchondral bone volume and turnover, and reduced Osteoarthritis Research Society International (OARSI) histopathological score in both 23- to 24-month-old male and female mice. Senolytics had little effect on 4 months old young mice, indicating age-specific benefits. Our study provides proof-of-concept evidence that age-related TMJ degeneration can be alleviated by pharmaceutical intervention targeting cellular senescence. Since the senolytics used in this study have been proven relatively safe in recent human studies, our findings may help justify future clinical trials addressing TMJ degeneration in old age.

Keywords:  TMJ; aging; cellular senescence; dasatinib; quercetin

DOI:  https://doi.org/10.1111/acel.13394
Aging Cell. 2021 Jun 08. e13415

Exercise reduces circulating biomarkers of cellular senescence in humans.

Davis A Englund, Ayumi E Sakamoto, Chad M Fritsche, Amanda A Heeren, Xu Zhang, Brian R Kotajarvi, Denise R Lecy, Matthew J Yousefzadeh, Marissa J Schafer, Thomas A White, Elizabeth J Atkinson, Nathan K LeBrasseur.

  Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

Keywords:  aging; immune cells; inflammation; senotherapeutics

DOI:  https://doi.org/10.1111/acel.13415
Science. 2021 Jun 08. pii: eabe4832. [Epub ahead of print]

Senolytics reduce coronavirus-related mortality in old mice.

Christina D Camell, Matthew J Yousefzadeh, Yi Zhu, Larissa G P Langhi Prata, Matthew A Huggins, Mark Pierson, Lei Zhang, Ryan D O'Kelly, Tamar Pirtskhalava, Pengcheng Xun, Keisuke Ejima, Ailing Xue, Utkarsh Tripathi, Jair Machado Espindola-Netto, Nino Giorgadze, Elizabeth J Atkinson, Christina L Inman, Kurt O Johnson, Stephanie H Cholensky, Timothy W Carlson, Nathan K LeBrasseur, Sundeep Khosla, M Gerard O'Sullivan, David B Allison, Stephen C Jameson, Alexander Meves, Ming Li, Y S Prakash, Sergio E Chiarella, Sara E Hamilton, Tamara Tchkonia, Laura J Niedernhofer, James L Kirkland, Paul D Robbins.

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting SnCs using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

DOI: https://doi.org/10.1126/science.abe4832
Nat Rev Immunol. 2021 Jun 07.

The role of T cells in age-related diseases.

Elisa Carrasco, Manuel M Gómez de Las Heras, Enrique Gabandé-Rodríguez, Gabriela Desdín-Micó, Juan Francisco Aranda, Maria Mittelbrunn.

Age-related T cell dysfunction can lead to failure of immune tolerance mechanisms, resulting in aberrant T cell-driven cytokine and cytotoxic responses that ultimately cause tissue damage. In this Review, we discuss the role of T cells in the onset and progression of age-associated conditions, focusing on cardiovascular disorders, metabolic dysfunction, neuroinflammation and defective tissue repair and regeneration. We present different mechanisms by which T cells contribute to inflammageing and might act as modulators of age-associated diseases, including through enhanced pro-inflammatory and cytotoxic activity, defective clearance of senescent cells or regulation of the gut microbiota. Finally, we propose that 'resetting' immune system tolerance or targeting pathogenic T cells could open up new therapeutic opportunities to boost resilience to age-related diseases.

DOI: https://doi.org/10.1038/s41577-021-00557-4
Aging (Albany NY). 2021 Jun 08. 13(undefined):

Acid ceramidase promotes senescent cell survival.

Rachel Munk, Carlos Anerillas, Martina Rossi, Dimitrios Tsitsipatis, Jennifer L Martindale, Allison B Herman, Jen-Hao Yang, Jackson A Roberts, Vijay R Varma, Poonam R Pandey, Madhav Thambisetty, Myriam Gorospe, Kotb Abdelmohsen.

  Cellular senescence is linked to chronic age-related diseases including atherosclerosis, diabetes, and neurodegeneration. Compared to proliferating cells, senescent cells express distinct subsets of proteins. In this study, we used cultured human diploid fibroblasts rendered senescent through replicative exhaustion or ionizing radiation to identify proteins differentially expressed during senescence. We identified acid ceramidase (ASAH1), a lysosomal enzyme that cleaves ceramide into sphingosine and fatty acid, as being highly elevated in senescent cells. This increase in ASAH1 levels in senescent cells was associated with a rise in the levels of ASAH1 mRNA and a robust increase in ASAH1 protein stability. Furthermore, silencing ASAH1 in pre-senescent fibroblasts decreased the levels of senescence proteins p16, p21, and p53, and reduced the activity of the senescence-associated β-galactosidase. Interestingly, depletion of ASAH1 in pre-senescent cells sensitized these cells to the senolytics Dasatinib and Quercetin (D+Q). Together, our study indicates that ASAH1 promotes senescence, protects senescent cells, and confers resistance against senolytic drugs. Given that inhibiting ASAH1 sensitizes cells towards senolysis, this enzyme represents an attractive therapeutic target in interventions aimed at eliminating senescent cells.

Keywords:  SASP; post-transcriptional; senescent cell metabolism; senotherapy; translational control

DOI:  https://doi.org/10.18632/aging.203170
JHEP Rep. 2021 Aug;3(4): 100301

Evaluating causality of cellular senescence in non-alcoholic fatty liver disease.

Abraham Stijn Meijnikman, Hilde Herrema, Torsten Pascal Marcel Scheithauer, Jeffrey Kroon, Max Nieuwdorp, Albert Kornelis Groen.

  Cellular senescence is a state of irreversible cell cycle arrest that has important physiological functions. However, cellular senescence is also a hallmark of ageing and has been associated with several pathological conditions. A wide range of factors including genotoxic stress, mitogens and inflammatory cytokines can induce senescence. Phenotypically, senescent cells are characterised by short telomeres, an enlarged nuclear area and damaged genomic and mitochondrial DNA. Secretion of proinflammatory proteins, also known as the senescence-associated secretory phenotype, is a characteristic of senescent cells that is thought to be the main contributor to their disease-inducing properties. In the past decade, the role of cellular senescence in the development of non-alcoholic fatty liver disease (NAFLD) and its progression towards non-alcoholic steatohepatitis (NASH) has garnered significant interest. Until recently, it was suggested that hepatocyte cellular senescence is a mere consequence of the metabolic dysregulation and inflammatory phenomena in fatty liver disease. However, recent work in rodents has suggested that senescence may be a causal factor in NAFLD development. Although causality is yet to be established in humans, current evidence suggests that targeting senescent cells has therapeutic potential for NAFLD. We aim to provide insights into the quality of the evidence supporting a causal role of cellular senescence in the development of NAFLD in rodents and humans. We will elaborate on key cellular and molecular features of senescence and discuss the efficacy and safety of novel senolytic drugs for the treatment or prevention of NAFLD.

Keywords:  ATM, ataxia telangiectasia mutated; C/EBPα, CCAAT- enhancer-binding protein; CDK, cyclin dependent kinase; DDR, DNA damage response; FFAs, free fatty acids; HCC, hepatocellular carcinoma; IL-, interleukin; KC, Kupffer cell; LSEC, liver sinusoidal endothelial cell; MCP1/CCL2, monocyte chemoattractant protein-1; MiDAS, mitochondrial dysfunction-associated senescence; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ROS, reactive oxygen species; Rb, retinoblastoma factor; SA-β gal, senescence-associated beta-galactosidase; SASP, senescence-associated secretory phenotype; SCAP, senescence-associated antiapoptotic pathways; TGFβ, transforming growth factor-β; TNFα, tumour necrosis factor-α; cellular senescence; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; obesity; qPCR, quantitative PCR; senolytics

DOI:  https://doi.org/10.1016/j.jhepr.2021.100301
Neurobiol Stress. 2021 Nov;15 100341

Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress.

Yu-Fen Lin, Li-Yun Wang, Chi-Sheng Chen, Chia-Chun Li, Ya-Hsin Hsiao.

  When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. Recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging. We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16INK4a was increased in the hippocampus, and senescence-associated β-galactosidase (SA-β-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-β-gal or p16INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits, suggesting that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline. Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits.

Keywords:  Cellular senescence; Chronic stress; Cognitive decline; Senolytics

DOI:  https://doi.org/10.1016/j.ynstr.2021.100341
J Cell Sci. 2021 Jun 01. pii: jcs256230. [Epub ahead of print]134(11):

Interferon regulatory factor 7 impairs cellular metabolism in aging adipose-derived stromal cells.

Alice Nodari, Ilaria Scambi, Daniele Peroni, Elisa Calabria, Donatella Benati, Silvia Mannucci, Marcello Manfredi, Andrea Frontini, Silvia Visonà, Andrea Bozzato, Andrea Sbarbati, Federico Schena, Emilio Marengo, Mauro Krampera, Mirco Galiè.

  Dysregulated immunity and widespread metabolic dysfunctions are the most relevant hallmarks of the passing of time over the course of adult life, and their combination at midlife is strongly related to increased vulnerability to diseases; however, the causal connection between them remains largely unclear. By combining multi-omics and functional analyses of adipose-derived stromal cells established from young (1 month) and midlife (12 months) mice, we show that an increase in expression of interferon regulatory factor 7 (IRF7) during adult life drives major metabolic changes, which include impaired mitochondrial function, altered amino acid biogenesis and reduced expression of genes involved in branched-chain amino acid (BCAA) degradation. Our results draw a new paradigm of aging as the 'sterile' activation of a cell-autonomous pathway of self-defense and identify a crucial mediator of this pathway, IRF7, as driver of metabolic dysfunction with age.

Keywords:  Aging; Branched-chain amino acid degradation; Cellular metabolism; IFN signaling; Interferon regulatory factor 7; Mitochondria

DOI:  https://doi.org/10.1242/jcs.256230
Ageing Res Rev. 2021 Jun 02. pii: S1568-1637(21)00123-9. [Epub ahead of print]70 101376

The Role of Rapamycin in Healthspan Extension via the Delay of Organ Aging.

Yan Zhang, Jinjin Zhang, Shixuan Wang.

  Aging can not only shorten a healthy lifespan, but can also lead to multi-organ dysfunction and failure. Anti-aging is a complex and worldwide conundrum for eliminating the various pathologies of senility. The past decade has seen great progress in the understanding of the aging-associated signaling pathways and their application for developing anti-aging approaches. Currently, some drugs can improve quality of life. The activation of mammalian target of rapamycin (mTOR) signaling is one of the core and detrimental mechanisms related to aging; rapamycin can reduce the rate of aging, improve age-related diseases by inhibiting the mTOR pathway, and prolong lifespan and healthspan effectively. However, the current evidence for rapamycin in lifespan extension and organ aging is fragmented and scattered. In this review, we summarize the efficacy and safety of rapamycin in prolonging a healthy lifespan by systematically alleviating aging in multiple organ systems, i.e., the nervous, urinary, digestive, circulatory, motor, respiratory, endocrine, reproductive, integumentary and immune systems, to provide a theoretical basis for the future clinical application of rapamycin in anti-aging.

Keywords:  Adverse effects; Healthspan; Organ aging; Rapamycin; mTOR signaling

DOI:  https://doi.org/10.1016/j.arr.2021.101376
Proc Natl Acad Sci U S A. 2021 Jun 15. pii: e2105465118. [Epub ahead of print]118(24):

STING inhibitors target the cyclic dinucleotide binding pocket.

Ze Hong, Jiahao Mei, Chenhui Li, Guohui Bai, Munire Maimaiti, Haiyang Hu, Wenying Yu, Li Sun, Lele Zhang, Dan Cheng, Yixian Liao, Senlin Li, Yanping You, Hongbin Sun, Jing Huang, Xing Liu, Judy Lieberman, Chen Wang.

  Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1 -/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

Keywords:  Aicardi–Goutières syndrome; SAVI; STING; antagonist; type I interferons

DOI:  https://doi.org/10.1073/pnas.2105465118
Exp Cell Res. 2021 Jun 06. pii: S0014-4827(21)00221-4. [Epub ahead of print] 112689

Lipid accumulation-induced hepatocyte senescence regulates the activation of hepatic stellate cells through the Nrf2-antioxidant response element pathway.

Huiyuan Yu, Xin Jiang, Fangyuan Dong, Fan Zhang, Xueying Ji, Mengjuan Xue, Fan Yang, Jie Chen, Xiaona Hu, Zhijun Bao.

  Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally. Elderly individuals are at a higher risk of developing NAFLD with severe clinical outcomes. Although NAFLD is closely related to liver aging, the role of hepatocyte senescence in the progression of NAFLD, especially in the development of fibrosis, is still unclear. The early stage of NAFLD is mainly characterized by lipid accumulation in hepatocytes, which could lead to severe oxidative stress, causing cellular senescence. In the present study, hepatocytes cultured in the presence of free fatty acids to induce lipid deposition were used as a hepatocyte senescence model in vitro. Senescent hepatocytes significantly increased the activation of co-cultured primary hepatic stellate cells (HSCs) and the expression of pro-fibrosis molecules. Moreover, the antioxidant regulator nuclear factor erythroid 2-related factor 2 (Nrf2) that was upregulated in senescent hepatocytes was found to be related to the activation of co-cultured HSCs. The Nrf2 agonist sulforaphane, which upregulated the transcriptional activity of the Nrf2-antioxidant response element (ARE) pathway, remarkably inhibited hepatocyte senescence and its activation effect on HSCs. However, the liver tissue obtained from non-alcoholic steatohepatitis (NASH) mice with Nrf2 knockdown showed decreased antioxidation and significant liver senescence and fibrosis. In conclusion, this study confirmed that lipid accumulation induces hepatocyte senescence, which leads to HSC activation and development of hepatic fibrosis. Increasing the activity of the Nrf2-ARE antioxidant pathway in senescent hepatocytes elicited the opposite effect, suggesting that targeting Nrf2 may prevent or delay the progression of aging-related liver fibrosis in NASH.

Keywords:  Nrf2; aging; hepatic fibrosis; non-alcoholic fatty liver disease; oxidative stress

DOI:  https://doi.org/10.1016/j.yexcr.2021.112689
Aging Cell. 2021 Jun 09. e13417

Advanced maternal age causes premature placental senescence and malformation via dysregulated α-Klotho expression in trophoblasts.

Zhi Chen, Liling Xiong, Huili Jin, Jiaxiao Yu, Xin Li, Huijia Fu, Li Wen, Hongbo Qi, Chao Tong, Richard Saffery, Mark D Kilby, Philip N Baker.

  Advanced maternal age (AMA) pregnancy is associated with higher risks of adverse perinatal outcomes, which may result from premature senescence of the placenta. α-Klotho is a well-known antiaging protein; however, its expression and effect on the placenta in AMA pregnancies have not yet been fully elucidated. The expression patterns of α-Klotho in mouse and human placentas from AMA pregnancies were determined by Western blotting and immunohistochemistry (IHC) staining. α-Klotho expression in JAR cells was manipulated to investigate its role in trophoblastic senescence, and transwell assays were performed to assess trophoblast invasion. The downstream genes regulated by α-Klotho in JAR cells were first screened by mRNA sequencing in α-Klotho-knockdown and control JAR cells and then validated. α-Klotho-deficient mice were generated by injecting klotho-interfering adenovirus (Ad-Klotho) via the tail vein on GD8.5. Ablation of α-Klotho resulted in not only a senescent phenotype and loss of invasiveness in JAR cells but also a reduction in the transcription of cell adhesion molecule (CAM) genes. Overexpression of α-Klotho significantly improved invasion but did not alter the expression of senescence biomarkers. α-Klotho-deficient mice exhibited placental malformation and, consequently, lower placental and fetal weights. In conclusion, AMA results in reduced α-Klotho expression in placental trophoblasts, therefore leading to premature senescence and loss of invasion (possibly through the downregulation of CAMs), both of which ultimately result in placental malformation and adverse perinatal outcomes.

Keywords:  advanced maternal age; placenta; senescence; trophoblast; α-klotho

DOI:  https://doi.org/10.1111/acel.13417
Front Cell Dev Biol. 2021 ;9 640200

Interphase Chromosomes in Replicative Senescence: Chromosome Positioning as a Senescence Biomarker and the Lack of Nuclear Motor-Driven Chromosome Repositioning in Senescent Cells.

Ishita S Mehta, Kumars Riyahi, Rita Torres Pereira, Karen J Meaburn, Martin Figgitt, Ian R Kill, Christopher H Eskiw, Joanna M Bridger.

  This study demonstrates, and confirms, that chromosome territory positioning is altered in primary senescent human dermal fibroblasts (HDFs). The chromosome territory positioning pattern is very similar to that found in HDFs made quiescent either by serum starvation or confluence; but not completely. A few chromosomes are found in different locations. One chromosome in particular stands out, chromosome 10, which is located in an intermediate location in young proliferating HDFs, but is found at the nuclear periphery in quiescent cells and in an opposing location of the nuclear interior in senescent HDFs. We have previously demonstrated that individual chromosome territories can be actively and rapidly relocated, with 15 min, after removal of serum from the culture media. These chromosome relocations require nuclear motor activity through the presence of nuclear myosin 1β (NM1β). We now also demonstrate rapid chromosome movement in HDFs after heat-shock at 42°C. Others have shown that heat shock genes are actively relocated using nuclear motor protein activity via actin or NM1β (Khanna et al., 2014; Pradhan et al., 2020). However, this current study reveals, that in senescent HDFs, chromosomes can no longer be relocated to expected nuclear locations upon these two types of stimuli. This coincides with a entirely different organisation and distribution of NM1β within senescent HDFs.

Keywords:  chromatin dynamics; chromosome 10; chromosome territories; genome organisation; nuclear motors; nuclear myosin 1β; replicative senescence (RS)

DOI:  https://doi.org/10.3389/fcell.2021.640200
Aging Dis. 2021 Jun;12(3): 764-785

Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death.

Laura Gennaccaro, Claudia Fuchs, Manuela Loi, Riccardo Pizzo, Sara Alvente, Chiara Berteotti, Leonardo Lupori, Giulia Sagona, Giuseppe Galvani, Antonia Gurgone, Alessandra Raspanti, Giorgio Medici, Marianna Tassinari, Stefania Trazzi, Elisa Ren, Roberto Rimondini, Tommaso Pizzorusso, Zoccoli Giovanna, Giustetto Maurizio, Ciani Elisabetta.

  CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene. Children affected by CDD display a clinical phenotype characterized by early-onset epilepsy, intellectual disability, motor impairment, and autistic-like features. Although the clinical aspects associated with CDKL5 mutations are well described in children, adults with CDD are still under-characterized. Similarly, most animal research has been carried out on young adult Cdkl5 knockout (KO) mice only. Since age represents a risk factor for the worsening of symptoms in many neurodevelopmental disorders, understanding age differences in the development of behavioral deficits is crucial in order to optimize the impact of therapeutic interventions. Here, we compared young adult Cdkl5 KO mice with middle-aged Cdkl5 KO mice, at a behavioral, neuroanatomical, and molecular level. We found an age-dependent decline in motor, cognitive, and social behaviors in Cdkl5 KO mice, as well as in breathing and sleep patterns. The behavioral decline in older Cdkl5 KO mice was not associated with a worsening of neuroanatomical alterations, such as decreased dendritic arborization or spine density, but was paralleled by decreased neuronal survival in different brain regions such as the hippocampus, cortex, and basal ganglia. Interestingly, we found increased β-galactosidase activity and DNA repair protein levels, γH2AX and XRCC5, in the brains of older Cdkl5 KO mice, which suggests that an absence of Cdkl5 accelerates neuronal senescence/death by triggering irreparable DNA damage. In summary, this work provides evidence that CDKL5 may play a fundamental role in neuronal survival during brain aging and suggests a possible worsening with age of the clinical picture in CDD patients.

Keywords:  CDKL5; DNA damage; XRCC5; neuronal death; neuronal senescence; γH2AX

DOI:  https://doi.org/10.14336/AD.2020.0827
Int J Chron Obstruct Pulmon Dis. 2021 ;16 1661-1675

Histone Deacetylase 2 Suppresses Skeletal Muscle Atrophy and Senescence via NF-κB Signaling Pathway in Cigarette Smoke-Induced Mice with Emphysema.

Chao Li, Zhaohui Deng, Guixian Zheng, Ting Xie, Xinyan Wei, Zengyu Huo, Jing Bai.

   Background: Exposure to cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD). CS not only causes chronic airway inflammation and lung damage but also is involved in skeletal muscle dysfunction (SMD). Previous studies have shown that histone deacetylase 2 (HDAC2) plays an important role in the progression of COPD. The aim of this study was to determine the role of HDAC2 in CS-induced skeletal muscle atrophy and senescence.
Methods: Gastrocnemius muscle weight and cross-sectional area (CSA) were measured in mice with CS-induced emphysema, and changes in the expression of atrophy-related markers and senescence-related markers were detected. In addition, the relationship between HDAC2 expression and skeletal muscle atrophy and senescence was also investigated.
Results: Mice exposed to CS for 24 weeks developed emphysema and gastrocnemius atrophy and exhibited a decrease in gastrocnemius weight and skeletal muscle cross-sectional area. In addition, the HDAC2 protein levels were significantly decreased while the levels of atrophy-associated markers, including MURF1 and MAFbx, and senescence-associated markers, including P53 and P21, were significantly increased in the gastrocnemius muscle. In vitro, the exposure of C2C12 cells to cigarette smoke extract (CSE) significantly increased the MAFbx and MURF1 protein levels and decreased the HDAC2 protein levels. Moreover, overexpression of HDAC2 significantly ameliorated CSE-induced atrophy and senescence and reversed the increased MURF1, MAFbx, P53, and P21 expression in C2C12 cells. In addition, CSE treatment significantly increased the IKK and NF-κB p65 protein levels, and PTDC (an NF-kB inhibitor) ameliorated atrophy and senescence.
Conclusion: Our findings suggest that HDAC2 plays an important role in CS-induced skeletal muscle atrophy and senescence, possibly through the NF-κB pathway.

Keywords:  atrophy; histone deacetylase 2; nuclear factor-ҡB; senescence; skeletal muscle

DOI:  https://doi.org/10.2147/COPD.S314640
Exp Cell Res. 2021 Jun 05. pii: S0014-4827(21)00211-1. [Epub ahead of print] 112679

Cell Stress during Development and Disease - Special Issue, Review article Balancing DNA repair to prevent ageing and cancer.

Eleanor Rachel Stead, Ivana Bjedov.

  DNA damage is a constant stressor to the cell. Persistent damage to the DNA over time results in an increased risk of mutation and an accumulation of mutations with age. Loss of efficient DNA damage repair can lead to accelerated ageing phenotypes or an increased cancer risk, and the trade-off between cancer susceptibility and longevity is often driven by the cell's response to DNA damage. High levels of mutations in DNA repair mutants often leads to excessive cell death and stem cell exhaustion which may promote premature ageing. Stem cells themselves have distinct characteristics that enable them to retain low mutation rates. However, when mutations do arise, stem cell clonal expansion can also contribute to age-related tissue dysfunction as well as heightened cancer risk. In this review, we will highlight increasing DNA damage and mutation accumulation as hallmarks common to both ageing and cancer. We will propose that anti-ageing interventions might be cancer preventative and discuss the mechanisms through which they may act.

Keywords:  DNA damage; DNA repair; ageing; cancer; chromatin; epigenetic; healthspan; lifespan; longevity; mutation; stem cells

DOI:  https://doi.org/10.1016/j.yexcr.2021.112679
Ageing Res Rev. 2021 Jun 04. pii: S1568-1637(21)00125-2. [Epub ahead of print]70 101378

Mitochondria: Their relevance during oocyte ageing.

Jiska van der Reest, Gustavo Nardini Cecchino, Marcia C Haigis, Paweł Kordowitzki.

  The oocyte is recognised as the largest cell in mammalian species and other multicellular organisms. Mitochondria represent a high proportion of the cytoplasm in oocytes and mitochondrial architecture is different in oocytes than in somatic cells, characterised by a rounder appearance and fragmented network. Although the number of mitochondria per oocyte is higher than in any other mammalian cell, their number and activity decrease with advancing age. Mitochondria integrate numerous processes essential for cellular function, such as metabolic processes related to energy production, biosynthesis, and waste removal, as well as Ca2+ signalling and reactive oxygen species (ROS) homeostasis. Further, mitochondria are responsible for the cellular adaptation to different types of stressors such as oxidative stress or DNA damage. When these stressors outstrip the adaptive capacity of mitochondria to restore homeostasis, it leads to mitochondrial dysfunction. Decades of studies indicate that mitochondrial function is multifaceted, which is reflected in the oocyte, where mitochondria support numerous processes during oocyte maturation, fertilization, and early embryonic development. Dysregulation of mitochondrial processes has been consistently reported in ageing and age-related diseases. In this review, we describe the functions of mitochondria as bioenergetic powerhouses and signal transducers in oocytes, how dysfunction of mitochondrial processes contributes to reproductive ageing, and whether mitochondria could be targeted to promote oocyte rejuvenation.

Keywords:  Metabolism; Mitochondria; Oocytes; Oxidative stress; Reproductive ageing

DOI:  https://doi.org/10.1016/j.arr.2021.101378
Cell Rep Med. 2021 May 18. 2(5): 100262

Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways.

Ramin Sedaghat Herati, Luisa Victoria Silva, Laura A Vella, Alexander Muselman, Cecile Alanio, Bertram Bengsch, Raj K Kurupati, Senthil Kannan, Sasikanth Manne, Andrew V Kossenkov, David H Canaday, Susan A Doyle, Hildegund C J Ertl, Kenneth E Schmader, E John Wherry.

  Humoral immune responses are dysregulated with aging, but the cellular and molecular pathways involved remain incompletely understood. In particular, little is known about the effects of aging on T follicular helper (Tfh) CD4 cells, the key cells that provide help to B cells for effective humoral immunity. We performed transcriptional profiling and cellular analysis on circulating Tfh before and after influenza vaccination in young and elderly adults. First, whole-blood transcriptional profiling shows that ICOS+CD38+ cTfh following vaccination preferentially enriches in gene sets associated with youth versus aging compared to other circulating T cell types. Second, vaccine-induced ICOS+CD38+ cTfh from the elderly had increased the expression of genes associated with inflammation, including tumor necrosis factor-nuclear factor κB (TNF-NF-κB) pathway activation. Finally, vaccine-induced ICOS+CD38+ cTfh display strong enrichment for signatures of underlying age-associated biological changes. These data highlight the ability to use vaccine-induced cTfh as cellular "biosensors" of underlying inflammatory and/or overall immune health.

Keywords:  CD4; NF-kB; T follicular helper; aging; cellular biosensors; influenza; network analysis; vaccine

DOI:  https://doi.org/10.1016/j.xcrm.2021.100262
EMBO Rep. 2021 Jun 08. e52032

Aneuploid senescent cells activate NF-κB to promote their immune clearance by NK cells.

Ruoxi W Wang, Sonia Viganò, Uri Ben-David, Angelika Amon, Stefano Santaguida.

  The immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance are thus critical for understanding how cancer cells are recognized and eliminated. Aneuploidy is a hallmark of cancer, and we previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by natural killer (NK) cells in vitro. However, the mechanisms underlying this process remained elusive. Here, using an in vitro NK cell killing system, we show that non-cell-autonomous mechanisms in aneuploid cells predominantly mediate their clearance by NK cells. Our data indicate that in untransformed aneuploid cells, NF-κB signaling upregulation is central to elicit this immune response. Inactivating NF-κB abolishes NK cell-mediated clearance of untransformed aneuploid cells. In cancer cell lines, NF-κB upregulation also correlates with the degree of aneuploidy. However, such upregulation in cancer cells is not sufficient to trigger NK cell-mediated clearance, suggesting that additional mechanisms might be at play during cancer evolution to counteract NF-κB-mediated immunogenicity.

Keywords:  NF-κB; aneuploidy; complex karyotypes; immune clearance; senescence

DOI:  https://doi.org/10.15252/embr.202052032
Cell Rep. 2021 Jun 08. pii: S2211-1247(21)00571-4. [Epub ahead of print]35(10): 109220

Bacterial genotoxins induce T cell senescence.

Sarah L Mathiasen, Laura Gall-Mas, Ioannis S Pateras, Sofia D P Theodorou, Martin R J Namini, Morten B Hansen, Océane C B Martin, Chella Krishna Vadivel, Konstantinos Ntostoglou, Deborah Butter, Michael Givskov, Carsten Geisler, Arne N Akbar, Vassilis G Gorgoulis, Teresa Frisan, Niels Ødum, Thorbjørn Krejsgaard.

  Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells-the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence.

Keywords:  ATM; DNA damage; T cells; bacteria; cytolethal distending toxin; genotoxins; inflammation; senescence; senescence-associated secretory phenotype; typhoid toxin

DOI:  https://doi.org/10.1016/j.celrep.2021.109220
Cancer Res. 2021 Jun 11. pii: canres.0321.2021. [Epub ahead of print]

Multiple Roles of IL-6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis.

Anat Shriki, Tali Lanton, Amir Sonnenblick, Orr Levkovitch-Siany, Dana Eidelshtein, Rinat Abramovitch, Nofar Rosenberg, Orit Pappo, Sharona Elgavish, Yuval Nevo, Rifaat Safadi, Amnon Peled, Stefan Rose-John, Eithan Galun, Jonathan H Axelrod.

Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the pro-inflammatory cytokine interleukin-6 (IL-6) is conventionally considered a crucial driving factor. Paradoxically, IL-6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL-6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL-6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL-6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of non-alcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL-6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding pro-tumorigenic NASH-associated phenotypes and by reinforcing the anti-tumorigenic effects of the SASP.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0321
Wound Repair Regen. 2021 Jun 11.

Myofibroblast fate plasticity in tissue repair and fibrosis: de-activation, apoptosis, senescence and reprogramming.

Wolfgang Merkt, Yan Zhou, Hongwei Han, David Lagares.

  In response to tissue injury, fibroblasts differentiate into professional repair cells called myofibroblasts, which orchestrate many aspects of the normal tissue repair program including synthesis, deposition and contraction of extracellular matrix proteins, leading to wound closure. Successful tissue repair responses involve termination of myofibroblast activities in order to prevent pathologic fibrotic scarring. Here, we discuss the cellular and molecular mechanisms limiting myofibroblast activities during physiological tissue repair, including myofibroblast de-activation, apoptosis, reprogramming and immune clearance of senescent myofibroblasts. In addition, we summarize pathological mechanisms leading to myofibroblast persistence and survival, a hallmark of fibrotic diseases. Finally, we discuss emerging anti-fibrotic therapies aimed at targeting myofibroblast fate such as senolytics, gene therapy, cellular immunotherapy and CAR-T cells.

Keywords:  Myofibroblast; apoptosis; cellular senescence; fate; fibrosis; plasticity; reprogramming; tissue repair

DOI:  https://doi.org/10.1111/wrr.12952
Aging Cell. 2021 Jun 06. e13383

Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution.

Estel Ramos-Marquès, Laura García-Mendívil, María Pérez-Zabalza, Hazel Santander-Badules, Sabarathinam Srinivasan, Juan Carlos Oliveros, Rafael Torres-Pérez, Alberto Cebollada, José María Vallejo-Gil, Pedro Carlos Fresneda-Roldán, Javier Fañanás-Mastral, Manuel Vázquez-Sancho, Marta Matamala-Adell, Juan Fernando Sorribas-Berjón, Javier André Bellido-Morales, Francisco Javier Mancebón-Sierra, Alexánder Sebastián Vaca-Núñez, Carlos Ballester-Cuenca, Manuel Jiménez-Navarro, José Manuel Villaescusa, Elisa Garrido-Huéscar, Margarita Segovia-Roldán, Aida Oliván-Viguera, Carlos Gómez-González, Gorka Muñiz, Emiliano Diez, Laura Ordovás, Esther Pueyo.

  Aging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA-associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA-based analyses uncover depleted cardiac-specific processes, among other relevant functions, that are undetected by CA. Twenty BA-related microRNAs are identified, and two of them highly heart-enriched that are present in plasma. We describe a microRNA-gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research.

Keywords:  biological aging; biomarkers; gene regulation network; heart aging; microRNA; transcriptomic age marker

DOI:  https://doi.org/10.1111/acel.13383
Ageing Res Rev. 2021 Jun 08. pii: S1568-1637(21)00135-5. [Epub ahead of print] 101388

Age-related amyloidosis outside the brain: A state-of-the-art review.

Masayoshi Tasaki, Francesca Lavatelli, Laura Obici, Konen Obayashi, Takeshi Miyamoto, Giampaolo Merlini, Giovanni Palladini, Yukio Ando, Mitsuharu Ueda.

  Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer's and Parkinson's diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid β protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins; the prevalence, clinical manifestations, and pathogenesis of amyloidosis; and recent advances in our understanding of age-related amyloidoses outside the brain.

Keywords:  Aging; Amyloid; Amyloidosis; Epidermal growth factor-containing fibulin-like extracellular matrix protein 1; Islet amyloid polypeptide; Transthyretin

DOI:  https://doi.org/10.1016/j.arr.2021.101388
Cell Rep. 2021 Jun 08. pii: S2211-1247(21)00579-9. [Epub ahead of print]35(10): 109228

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology.

Yanling Hu, Gemma L Fryatt, Mohammadmersad Ghorbani, Juliane Obst, David A Menassa, Maria Martin-Estebane, Tim A O Muntslag, Adrian Olmos-Alonso, Monica Guerrero-Carrasco, Daniel Thomas, Mark S Cragg, Diego Gomez-Nicola.

  The sustained proliferation of microglia is a key hallmark of Alzheimer's disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased βgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aβ pathology in AD.

Keywords:  APP/PS1; Alzheimer's disease; CSF1R; disease-associated microglia (DAM)

DOI:  https://doi.org/10.1016/j.celrep.2021.109228
Aging Cell. 2021 Jun 07. e13408

Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.

Tara R Richman, Judith A Ermer, Stefan J Siira, Irina Kuznetsova, Christopher A Brosnan, Giulia Rossetti, Jessica Baker, Kara L Perks, Henrietta Cserne Szappanos, Helena M Viola, Nicola Gray, Mark Larance, Livia C Hool, Steven Zuryn, Oliver Rackham, Aleksandra Filipovska.

  Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep / ep ) or hyper-accurate (Mrps12ha / ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep / ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha / ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging.

Keywords:  ageing; metabolism; mitochondria; protein synthesis

DOI:  https://doi.org/10.1111/acel.13408
Geroscience. 2021 Jun 08.

Are fat and sugar just as detrimental in old age?

Ana P Valencia, Nitin Nagaraj, Deena H Osman, Peter S Rabinovitch, David J Marcinek.

  Aging and poor nutrition are independent risk factors for the development of chronic disease. When young animals are given diets high in fat or sugar, they exhibit hallmarks of aging like mitochondrial dysfunction and inflammation, and also develop a greater risk for age-related disease. The same mitochondrial dysfunction and inflammation that progress with aging may also further predispose older individuals to dietary insults by fat and sugar. The purpose of this work is to review the most recent studies that address the impact of fat and sugar consumption on hallmarks of aging (mitochondrial dysfunction and inflammation). Findings from these studies show that obesogenic, high-fat diets can exacerbate age-related disease and hallmarks of aging in young animals, but high-fat diets that are non-obesogenic may play a beneficial role in old age. In contrast, high-sugar diets do not require an obesogenic effect to induce mitochondrial dysfunction or inflammation in young rodents. Currently, there is a lack of experimental studies addressing the impact of sugar in the context of aging, even though empirical evidence points to the detrimental effect of sugar in aging by contributing to a variety of age-related diseases. Fig. 1 Mitochondrial dysfunction and altered cellular communication (e.g. inflammation) progress with advancing age and increase the risk for age-related disease (ARD). Given the physiological changes that occur with age, the impact of high-fat (HFD) and high-sugar diets (HSD) may differ in later and earlier stages of life. HFD can promote the development of hallmarks of aging in young animals and can also exacerbate the risk for ARD when consumed at an old age. However, non-obesogenic high-fat diets may also reduce the risk for ARD in old age by acting on these hallmarks of aging. On the other hand, HSD promotes mitochondrial dysfunction and inflammation without necessarily inducing weight gain in young animals. Empirical evidence points to sugar as a major contributor to age-related disease and more experimental studies are needed to clarify whether aged individuals are more susceptible to its effects.

Keywords:  Fructose; Inflammation; Ketogenic; Mitochondrial dysfunction; Obesity; Old age; Sucrose

DOI:  https://doi.org/10.1007/s11357-021-00390-6
Immun Ageing. 2021 Jun 07. 18(1): 27

Systemic transplantation of adult multipotent stem cells prevents articular cartilage degeneration in a mouse model of accelerated ageing.

Seth D Thompson, Rajeswari Pichika, Richard L Lieber, Mitra Lavasani.

   BACKGROUND: Osteoarthritis (OA) is one of the most prevalent joint diseases of advanced age and is a leading cause of disability worldwide. Ageing is a major risk factor for the articular cartilage (AC) degeneration that leads to OA, and the age-related decline in regenerative capacity accelerates OA progression. Here we demonstrate that systemic transplantation of a unique population of adult multipotent muscle-derived stem/progenitor cells (MDSPCs), isolated from young wild-type mice, into Zmpste24-/- mice (a model of Hutchinson-Gilford progeria syndrome, a condition marked by accelerated ageing), prevents ageing-related homeostatic decline of AC.
RESULTS: MDSPC treatment inhibited expression of cartilage-degrading factors such as pro-inflammatory cytokines and extracellular matrix-proteinases, whereas pro-regenerative markers associated with cartilage mechanical support and tensile strength, cartilage resilience, chondrocyte proliferation and differentiation, and cartilage growth, were increased. Notably, MDSPC transplantation also increased the expression level of genes known for their key roles in immunomodulation, autophagy, stress resistance, pro-longevity, and telomere protection. Our findings also indicate that MDSPC transplantation increased proteoglycan content by regulating chondrocyte proliferation.
CONCLUSIONS: Together, these findings demonstrate the ability of systemically transplanted young MDSPCs to preserve a healthy homeostasis and promote tissue regeneration at the molecular and tissue level in progeroid AC. These results highlight the therapeutic potential of systemically delivered multipotent adult stem cells to prevent age-associated AC degeneration.

Keywords:  Accelerated ageing; Adult stem cells; Articular cartilage; Progeria; Regenerative medicine; Transplantation

DOI:  https://doi.org/10.1186/s12979-021-00239-8
NPJ Regen Med. 2021 Jun 11. 6(1): 34

Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice.

Yueying Zhou, Xiaonan Xin, Lichao Wang, Binsheng Wang, Li Chen, Ousheng Liu, David W Rowe, Ming Xu.

The osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) declines dramatically with aging. By using a calvarial defect model, we showed that a senolytic cocktail (dasatinib+quercetin; D + Q) improved osteogenic capacity of aged BMSC both in vitro and in vivo. The study presented a model to assess strategies to improve bone-forming potential on aged BMSCs. D + Q might hold promise for improving BMSC function in aged populations.

DOI: https://doi.org/10.1038/s41536-021-00145-z
Autophagy. 2021 Jun 09. 1-3

Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging.

Sebastian J Hofer, YongTian Liang, Andreas Zimmermann, Sabrina Schroeder, Jörn Dengjel, Guido Kroemer, Tobias Eisenberg, Stephan J Sigrist, Frank Madeo.

  Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice. In two adjacent studies, we explored how dietary spermidine supplementation enhances eEF5/EIF5A hypusination, cerebral mitochondrial function and cognition in aging Drosophila melanogaster and mice.

Keywords:  Autophagy; Drosophila; Pink1; hypusination; learning; memory; mitophagy; polyamines; spermidine

DOI:  https://doi.org/10.1080/15548627.2021.1933299
Cell Death Dis. 2021 Jun 08. 12(6): 594

G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence.

Shu-Ning Sun, Shi-Hao Ni, Yue Li, Xin Liu, Jian-Ping Deng, Zi-Xin Chen, Huan Li, Wen-Jun Feng, Yu-Sheng Huang, Da-Nian Li, Shao-Xiang Xian, Zhong-Qi Yang, Ling-Jun Wang, Lu Lu.

Aging is one of the most prominent risk factors for heart failure. Myeloid-derived suppressor cells (MDSCs) accumulate in aged tissue and have been confirmed to be associated with various aging-related diseases. However, the role of MDSCs in the aging heart remains unknown. Through RNA-seq and biochemical approaches, we found that granulocytic MDSCs (G-MDSCs) accumulated significantly in the aging heart compared with monocytic MDSCs (M-MDSCs). Therefore, we explored the effects of G-MDSCs on the aging heart. We found that the adoptive transfer of G-MDSCs of aging mice to young hearts resulted in cardiac diastolic dysfunction by inducing cardiac fibrosis, similar to that in aging hearts. S100A8/A9 derived from G-MDSCs induced inflammatory phenotypes and increased the osteopontin (OPN) level in fibroblasts. The upregulation of fibroblast growth factor 2 (FGF2) expression in fibroblasts mediated by G-MDSCs promoted antisenescence and antiapoptotic phenotypes of fibroblasts. SOX9 is the downstream gene of FGF2 and is required for FGF2-mediated and G-MDSC-mediated profibrotic effects. Interestingly, both FGF2 levels and SOX9 levels were upregulated in fibroblasts but not in G-MDSCs and were independent of S100A8/9. Therefore, a novel FGF2-SOX9 signaling axis that regulates fibroblast self-renewal and antiapoptotic phenotypes was identified. Our study revealed the mechanism by which G-MDSCs promote cardiac fibrosis via the secretion of S100A8/A9 and the regulation of FGF2-SOX9 signaling in fibroblasts during aging.

DOI: https://doi.org/10.1038/s41419-021-03874-7