bims-senagi 2022-04-03 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–04–03
33 papers selected by
Maria Grazia Vizioli, Mayo Clinic

Cell senescence, rapamycin and hyperfunction theory of aging.
The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?
Identification of gingerenone A as a novel senolytic compound.
Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity.
Circulating biomarkers of inflammaging as potential predictors of COVID-19 severe outcomes.
cGAS-STING mediates cytoplasmic mitochondrial-DNA-induced inflammatory signal transduction during accelerated senescence of pancreatic β-cells induced by metabolic stress.
Ceramide-1-Phosphate Is Involved in Therapy-Induced Senescence.
Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration.
Avenanthramide C induces cellular senescence in colorectal cancer cells via suppressing β-catenin-mediated the transcription of miR-183/96/182 cluster.
Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after G2 arrest.
Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine.
Microbiota-microglia connections in age-related cognition decline.
p38α Deficiency in T Cells Ameliorates Diet-Induced Obesity, Insulin Resistance and Adipose Tissue Senescence.
Role of Senescence in Tumorigenesis and Anticancer Therapy.
System-level metabolic modeling facilitates unveiling metabolic signature in exceptional longevity.
Targeting anxiety and senescence with senolytics.
Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche.
Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.
Prp19 Facilitated p21-Dependent Senescence of Hepatocellular Carcinoma Cells.
Advanced Oxidative Protein Products Drive Trophoblast Cells Into Senescence by Inhibiting the Autophagy: The Potential Implication of Preeclampsia.
Noncoding RNAs in age-related cardiovascular diseases.
ROR2 Downregulation Activates the MSX2/NSUN2/p21 Regulatory Axis and Promotes Dental Pulp Stem Cell Senescence.
Alzheimer-like tau accumulation in dentate gyrus mossy cells induces spatial cognitive deficits by disrupting multiple memory-related signaling and inhibiting local neural circuit.
Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets.
Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration.
The p53 network: cellular and systemic DNA damage responses in cancer and aging.
Roles of Long Non-coding RNAs in the Development of Aging-Related Neurodegenerative Diseases.
Trimethylamine N-oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model.
Oxysterols are potential physiological regulators of ageing.
Protective role of chaperone-mediated autophagy against atherosclerosis.
Ageing is associated with maladaptive immune response and worse outcome after traumatic brain injury.
Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription.
E-cadherin deficiency promotes prostate macrophage inflammation and bladder overactivity in aged male mice.

Cell Cycle. 2022 Mar 31. 1-12

Cell senescence, rapamycin and hyperfunction theory of aging.

Mikhail V Blagosklonny.

  A hallmark of cellular senescence is proliferation-like activity of growth-promoting pathways (such as mTOR and MAPK) in non-proliferating cells. When the cell cycle is arrested, these pathways convert arrest to senescence (geroconversion), rendering cells hypertrophic, beta-Gal-positive and hyperfunctional. The senescence-associated secretory phenotype (SASP) is one of the numerous hyperfunctions. Figuratively, geroconversion is a continuation of growth in non-proliferating cells. Rapamycin, a reversible inhibitor of growth, slows down mTOR-driven geroconversion. Developed two decades ago, this model had accurately predicted that rapamycin must extend life span of animals. However, the notion that senescent cells directly cause organismal aging is oversimplified. Senescent cells contribute to organismal aging but are not strictly required. Cell senescence and organismal aging can be linked indirectly via the same underlying cause, namely hyperfunctional signaling pathways such as mTOR.

Keywords:  Senescence; geroconversion; geroscience; gerostatics; healthspan; rapalogs; sirolimus

DOI:  https://doi.org/10.1080/15384101.2022.2054636
Inflamm Regen. 2022 Apr 02. 42(1): 11

The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?

Naoko Ohtani.

  Cellular senescence is a state of irreversible cell cycle arrest that can be induced by a variety of potentially oncogenic stimuli, including DNA damage. Hence, senescence has long been considered to suppress tumorigenesis, acting as a guardian of homeostasis. However, recent studies have revealed that senescent cells exhibit the secretion of a series of inflammatory cytokines, chemokines, growth factors, and matrix remodeling factors that alter the local tissue environment and contribute to chronic inflammation and cancer. This senescence phenotype is termed as senescence-associated secretory phenotype (SASP) and is observed not only in cultured cells in vitro but also in vivo. Recently, the physiological and pathological roles of SASP have been increasingly clarified. Notably, several studies have reported that the intrinsic mechanism of SASP factor production is predominantly mediated through the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway by aberrantly accumulated DNA fragments from the nucleus of senescent cells. In contrast, various extrinsic triggers of SASP also exist in vivo, for example, the SASP induction in hepatic stellate cells in the tumor microenvironment of obesity-associated liver cancer by the translocated gut microbial metabolites. Recently, the strategy for the elimination of senescent cells (senolysis) has attracted increasing attention. Thus, the role of SASP and the effects and outcomes of senolysis in vivo will be also discussed in this review.

Keywords:  Cellular senescence; Senescence-associated secretory phenotype; Senolysis; Toll-like receptor; Tumor microenvironment; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s41232-022-00197-8
PLoS One. 2022 ;17(3): e0266135

Identification of gingerenone A as a novel senolytic compound.

Ruin Moaddel, Martina Rossi, Stephanie Rodriguez, Rachel Munk, Mohammed Khadeer, Kotb Abdelmohsen, Myriam Gorospe, Luigi Ferrucci.

Senescent cells accumulate with aging and have been shown to contribute to age-associated diseases and organ dysfunction. Eliminating senescent cells with senolytic drugs has been shown to improve age phenotypes in mouse models and there is some initial evidence that it may improve the health of persons with chronic diseases. In this study, we employed WI-38 human fibroblasts rendered senescent by exposure to ionizing radiation (IR) to screen several plant extracts for their potential senolytic and/or senomorphic activity. Of these, ginger extract (Zingiber officinale Rosc.) selectively caused the death of senescent cells without affecting proliferating cells. Among the major individual components of ginger extract, gingerenone A and 6-shogaol showed promising senolytic properties, with gingerenone A selectively eliminating senescent cells. Similar to the senolytic cocktail dasatinib and quercetin (D+Q), gingerenone A and 6-shogaol elicited an apoptotic program. Additionally, both D+Q and gingerenone A had a pronounced effect on suppressing the senescence-associated secretory phenotype (SASP). Gingerenone A selectively promotes the death of senescent cells with no effect on non-senescent cells and these characteristics strongly support the idea that this natural compound may have therapeutic benefit in diseases characterized by senescent cell accumulation.

DOI: https://doi.org/10.1371/journal.pone.0266135
Aging Cell. 2022 Apr 01. e13602

Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity.

Abhishek Chandra, Anthony B Lagnado, Joshua N Farr, Madison Doolittle, Tamara Tchkonia, James L Kirkland, Nathan K LeBrasseur, Paul D Robbins, Laura J Niedernhofer, Yuji Ikeno, João F Passos, David G Monroe, Robert J Pignolo, Sundeep Khosla.

  Cellular senescence, which is a major cause of tissue dysfunction with aging and multiple other conditions, is known to be triggered by p16Ink4a or p21Cip1 , but the relative contributions of each pathway toward inducing senescence are unclear. Here, we directly addressed this issue by first developing and validating a p21-ATTAC mouse with the p21Cip1 promoter driving a "suicide" transgene encoding an inducible caspase-8 which, upon induction, selectively kills p21Cip1 -expressing senescent cells. Next, we used the p21-ATTAC mouse and the established p16-INK-ATTAC mouse to directly compare the contributions of p21Cip1 versus p16Ink4a in driving cellular senescence in a condition where a tissue phenotype (bone loss and increased marrow adiposity) is clearly driven by cellular senescence-specifically, radiation-induced osteoporosis. Using RNA in situ hybridization, we confirmed the reduction in radiation-induced p21Cip1 - or p16Ink4a -driven transcripts following senescent cell clearance in both models. However, only clearance of p21Cip1 +, but not p16Ink4a +, senescent cells prevented both radiation-induced osteoporosis and increased marrow adiposity. Reduction in senescent cells with dysfunctional telomeres following clearance of p21Cip1 +, but not p16Ink4a +, senescent cells also reduced several of the radiation-induced pro-inflammatory senescence-associated secretory phenotype factors. Thus, by directly comparing senescent cell clearance using two parallel genetic models, we demonstrate that radiation-induced osteoporosis is driven predominantly by p21Cip1 - rather than p16Ink4a -mediated cellular senescence. Further, this approach can be used to dissect the contributions of these pathways in other senescence-associated conditions, including aging across tissues.

Keywords:  bone; radiation; senescence

DOI:  https://doi.org/10.1111/acel.13602
Mech Ageing Dev. 2022 Mar 25. pii: S0047-6374(22)00049-5. [Epub ahead of print]204 111667

Circulating biomarkers of inflammaging as potential predictors of COVID-19 severe outcomes.

Jacopo Sabbatinelli, Giulia Matacchione, Angelica Giuliani, Deborah Ramini, Maria Rita Rippo, Antonio Domenico Procopio, Massimiliano Bonafè, Fabiola Olivieri.

  The COVID-19 pandemic caused by SARS-CoV-2 infection has been of unprecedented clinical and socio-economic worldwide relevance. The case fatality rate for COVID-19 grows exponentially with age and the presence of comorbidities. In the older patients, COVID-19 manifests predominantly as a systemic disease associated with immunological, inflammatory, and procoagulant responses. Timely diagnosis and risk stratification are crucial steps to define appropriate therapies and reduce mortality, especially in the older patients. Chronically and systemically activated innate immune responses and impaired antiviral responses have been recognized as the results of a progressive remodeling of the immune system during aging, which can be described by the words 'immunosenescence' and 'inflammaging'. These age-related features of the immune system were highlighted in patients affected by COVID-19 with the poorest clinical outcomes, suggesting that the mechanisms underpinning immunosenescence and inflammaging could be relevant for COVID-19 pathogenesis and progression. Increasing evidence suggests that senescent myeloid and endothelial cells are characterized by the acquisition of a senescence-associated pro-inflammatory phenotype (SASP), which is considered as the main culprit of both immunosenescence and inflammaging. Here, we reviewed this evidence and highlighted several circulating biomarkers of inflammaging that could provide additional prognostic information to stratify COVID-19 patients based on the risk of severe outcomes.

Keywords:  Biomarkers; COVID-19; Inflammaging; Neutrophils; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.mad.2022.111667
FASEB J. 2022 May;36(5): e22266

cGAS-STING mediates cytoplasmic mitochondrial-DNA-induced inflammatory signal transduction during accelerated senescence of pancreatic β-cells induced by metabolic stress.

Huiqing Hu, Ruxing Zhao, Qin He, Chen Cui, Jia Song, Xinghong Guo, Nan Zang, Mengmeng Yang, Ying Zou, Jingwen Yang, Jinquan Li, Liming Wang, Longqing Xia, Lingshu Wang, Falian He, Xinguo Hou, Fei Yan, Li Chen.

  Type 2 diabetes mellitus (T2DM) is an age-related disease characterized by impaired pancreatic β cell function and insulin resistance. Recent studies have shown that the accumulation of senescent β cells under metabolic stress conditions leads to the progression of T2DM, while senolysis can improve the prognosis. However, the specific mechanism of β cell senescence is still unclear. In this study, we found that the increased load of senescence pancreatic β cells in both older mice and obese mice induced by high-fat diet (HFD) (DIO mice) was accompanied by activation of the Cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway and using cGAS or STING small interfering RNA or STING inhibitor C176 to downregulate this pathway reduced the senescence-associated secretion profile (SASP) and senescence of Min6 cells treated with palmitic acid or hydrogen peroxide. C176 intervention in DIO mice also significantly reduced the inflammation and senescence of the islets, thereby protecting the function of pancreatic β cell and glucose metabolism. Our study further revealed that mitochondrial DNA (mtDNA) leakage under metabolic stress conditions was critical for the activation of the cGAS-STING pathway, which can be reversed by the mtDNA depleting agent ethidium bromide. Consistently, mtDNA leakage was more severe in older mice and was accelerated by a chronic HFD. In conclusion, we demonstrate that cytoplasmic mtDNA activates the cGAS-STING pathway to mediate SASP during the accelerated senescence of pancreatic β-cells induced by metabolic stress, and this process can be downregulated by the STING inhibitor C176.

Keywords:  SASP; cGAS-STING pathway; pancreatic β cell function; senescence; type 2 diabetes mellitus

DOI:  https://doi.org/10.1096/fj.202101988R
ACS Chem Biol. 2022 Mar 30.

Ceramide-1-Phosphate Is Involved in Therapy-Induced Senescence.

Alec Millner, Logan Running, Nicole Colon-Rosa, Diana S Aga, Jonna Frasor, G Ekin Atilla-Gokcumen.

Sphingolipids are key signaling lipids and their dysregulation has been associated with various cellular processes. We have previously shown significant changes in sphingolipids in therapy-induced senescence, a state of cell cycle arrest as a response to chemotherapy, including the accumulation of ceramides, and provided evidence suggesting that ceramide processing is important for this process. Herein, we conducted a focused small molecule inhibitor screen targeting the sphingolipid pathway, which highlighted a new lipid regulator of therapy-induced senescence. Among the inhibitors tested, the inhibition of ceramide kinase by NVP-231 reduced the levels of senescent cells. Ceramide kinase knockdown exhibited similar effects, strongly supporting the involvement of ceramide kinase during this process. We showed that ceramide-1-phosphate was upregulated in therapy-induced senescence and that NVP-231 reduced ceramide-1-phosphate levels in different cell line models of therapy-induced senescence. Finally, ceramide-1-phosphate addition to NVP-231-treated cells reversed the effects of NVP-231 during senescence. Overall, our results identify a previously unknown lipid player in therapy-induced senescence and highlight a potential targetable enzyme to reduce the levels of therapy-induced senescent cells.

DOI: https://doi.org/10.1021/acschembio.2c00216
Aging Cell. 2022 Mar 29. e13603

Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration.

Mamta Rai, Michelle Curley, Zane Coleman, Fabio Demontis.

  Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age-associated diseases. The ubiquitin-proteasome and autophagy-lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age-related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy-lysosome and ubiquitin-proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age-related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age-related neurodegeneration.

Keywords:  aging; extracellular proteostasis; neurodegeneration; peptidase; protease; proteolysis

DOI:  https://doi.org/10.1111/acel.13603
Biochem Pharmacol. 2022 Mar 28. pii: S0006-2952(22)00115-0. [Epub ahead of print] 115021

Avenanthramide C induces cellular senescence in colorectal cancer cells via suppressing β-catenin-mediated the transcription of miR-183/96/182 cluster.

Rong Fu, Zhangfeng Dou, Ning Li, Jinqi Zhang, Zhuoyu Li, Peng Yang.

  Cellular senescence is representing a potential anticancer therapeutic arsenal. Avenanthramide C (AVN C), as signature compounds of oats, exhibits antioxidant, anti-inflammatory, anti-atherosclerotic, and anti-tumor activities. However, the relationship between AVN C and cellular senescence in tumors remains largely unclear. Here, we elucidated that AVN C treatment predisposed colorectal cancer cells to senescent phenotype confirmed by flattened and enlarged shape characteristics, elevated senescence-associated β-galactosidase (SA-β-Gal) activity, and G1 phase arrest. Furthermore, AVN C triggered cellular senescence via transcriptionally repressing miR-183/96/182 cluster and subsequently reduced the levels of mature miR-183, -96, and -182. Mechanistically, AVN C exerted its senescence induction by attenuating β-catenin-mediated transactivation of miR-183/96/182 cluster to unleash its common target FOXO1 and two other targets, FOXO3 and SMAD4, which subsequently foster the p21 and p16 expression. In addition, AVN C is also noted to facilitate p53-mediated p21 transactivation via suppressing β-catenin. Collectively, we identified a novel mechanism of β-catenin/miR-183/96/182 cluster/FOXO1 mediated-CRC cellular senescence that entails that AVN C serves as an auxiliary agent for CRC treatment.

Keywords:  Avenanthramide C; cellular senescence; colorectal cancer; miR-183/96/182 cluster

DOI:  https://doi.org/10.1016/j.bcp.2022.115021
J Cell Sci. 2022 Mar 28. pii: jcs.259114. [Epub ahead of print]

Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after G2 arrest.

Gerald Lossaint, Anđela Horvat, Véronique Gire, Katarina Bacevic, Karim Mrouj, Fabienne Charrier-Savournin, Virginie Georget, Daniel Fisher, Vjekoslav Dulic.

  Senescence is an irreversible proliferation withdrawal that can be initiated after DNA damage-induced cell cycle arrest in G2 phase to prevent genomic instability. Senescence onset in G2 requires p53 and RB family tumour suppressors, but how they are regulated to convert a temporary cell cycle arrest into a permanent one remains unknown. Here, we show that a previously unrecognised balance between the CDK inhibitor p21 and Chk1 controls D-type cyclin-CDK activity during G2 arrest. In non-transformed cells, p21 activates RB in G2 by inhibiting Cyclin D1-CDK2/CDK4. The resulting G2 exit, which precedes appearance of senescence markers, is associated with a mitotic bypass, Chk1 downregulation and DNA damage foci reduction. In p53/RB-proficient cancer cells, compromised G2 exit correlates with sustained Chk1 activity, delayed p21 induction, untimely Cyclin E1 re-expression and genome reduplication. Conversely, Chk1 depletion promotes senescence by inducing p21 binding to Cyclin D1 and Cyclin E1-CDK complexes and down-regulating CDK6, whereas Chk2 knockdown enables RB phosphorylation and delays G2 exit. In conclusion, p21 and Chk2 oppose Chk1 to maintain RB activity, thus promoting DNA damage-induced senescence onset in G2.

Keywords:  CDK6; Chk1; DNA damage checkpoints; G2 arrest after DNA damage; Senescence; p21

DOI:  https://doi.org/10.1242/jcs.259114
Aging (Albany NY). 2022 Mar 29. 14(undefined):

Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine.

Frank W Pun, Geoffrey Ho Duen Leung, Hoi Wing Leung, Bonnie Hei Man Liu, Xi Long, Ivan V Ozerov, Ju Wang, Feng Ren, Alexander Aliper, Evgeny Izumchenko, Alexey Moskalev, João Pedro de Magalhães, Alex Zhavoronkov.

  Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation and activation of retrotransposons are also often considered, given their strong association with aging. In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases. Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.

Keywords:  artificial intelligence; deep learning; drug discovery; multi-omics; target identification

DOI:  https://doi.org/10.18632/aging.203960
Aging Cell. 2022 Mar 29. e13599

Microbiota-microglia connections in age-related cognition decline.

Rui Zhou, Shufang Qian, William C S Cho, Jinyun Zhou, Chentao Jin, Yan Zhong, Jing Wang, Xiaohui Zhang, Zhoujiao Xu, Mei Tian, Lawrence W C Chan, Hong Zhang.

  Aging is an inevitable process that all individuals experience, of which the extent differs among individuals. It has been recognized as the risk factor of neurodegenerative diseases by affecting gut microbiota compositions, microglia, and cognition abilities. Aging-induced changes in gut microbiota compositions have a critical role in orchestrating the morphology and functions of microglia through the gut-brain axis. Gut microbiota communicates with microglia by its secreted metabolites and neurotransmitters. This is highly associated with age-related cognitive declines. Here, we review the main composition of microbiota in the aged individuals, outline the changes of the brain in age-related cognitive decline from a neuroinflammation perspective, especially the changes of morphology and functions of microglia, discuss the crosstalk between microbiota and microglia in the aged brain and further highlight the role of microbiota-microglia connections in neurodegenerative diseases (Alzheimer's disease and Parkinson's disease).

Keywords:  cognitive aging; gut microbiota; microglia; neuroinflammation

DOI:  https://doi.org/10.1111/acel.13599
Diabetes. 2022 Mar 29. pii: db210653. [Epub ahead of print]

p38α Deficiency in T Cells Ameliorates Diet-Induced Obesity, Insulin Resistance and Adipose Tissue Senescence.

Deyun Meng, Baohua Zhang, Yanyan Wang, Tingting Zheng, Ran Hu, Bin Wang, Kinya Otsu, Ying Wang, Gonghua Huang.

Adipose tissue-resident T cells play vital roles in regulating inflammation and metabolism in obesity, but the underlying mechanisms remain unclear. Here, we showed that high-fat diet (HFD) feeding enhances p38 activity in adipose-resident T cells. T cell-specific deletion of p38α, an essential subunit of p38 expressed in most of immune cells, protected mice from HFD-induced obesity, hepatic steatosis, adipose tissue inflammation and insulin resistance. Mice with p38α deletion in T cells exhibited higher energy expenditure. Mechanistically, p38α promoted T cell glycolysis through mTOR signaling, leading to enhanced Th1 differentiation. Accordingly, genetic deletion of p38α alleviated the ongoing diet-induced obesity. Unexpectedly, p38α signaling in T cells promoted adipose tissue senescence during obesity and aging. Taken together, our results identify p38α in T cells as an essential regulator of obesity, insulin resistance and adipose tissue senescence, and p38α may be a therapeutic target for obese- or aging-associated diseases.

DOI: https://doi.org/10.2337/db21-0653
J Oncol. 2022 ;2022 5969536

Role of Senescence in Tumorigenesis and Anticancer Therapy.

Ewelina Stoczynska-Fidelus, Marta Węgierska, Amelia Kierasińska, Damian Ciunowicz, Piotr Rieske.

Although the role of senescence in many physiological and pathological processes is becoming more identifiable, many aspects of senescence are still enigmatic. A special attention is paid to the role of this phenomenon in tumor development and therapy. This review mainly deals with a large spectrum of oncological issues, beginning with therapy-induced senescence and ending with oncogene-induced senescence. Moreover, the role of senescence in experimental approaches, such as primary cancer cell culture or reprogramming into stem cells, is also beginning to receive further consideration. Additional focus is made on senescence resulting from mitotic catastrophe processes triggered by events occurring during mitosis and jeopardizing chromosomal stability. It has to be also realized that based on recent findings, the basics of senescent cell property interpretation, such as irreversibility of proliferation blockade, can be undermined. It shows that the definition of senescence probably requires updating. Finally, the role of senescence is lately more understandable in the immune system, especially since senescence can diminish the effectiveness of the chimeric antigen receptor T-cell (CAR-T) therapy. In this review, we summarize the current knowledge regarding all these issues.

DOI: https://doi.org/10.1155/2022/5969536
Aging Cell. 2022 Mar 27. e13595

System-level metabolic modeling facilitates unveiling metabolic signature in exceptional longevity.

Gong-Hua Li, Feifei Han, Fu-Hui Xiao, Kang-Su-Yun Gu, Qiu Shen, Weihong Xu, Wen-Xing Li, Yan-Li Wang, Bin Liang, Jing-Fei Huang, Wenzhong Xiao, Qing-Peng Kong.

  Although it is well known that metabolic control plays a crucial role in regulating the health span and life span of various organisms, little is known for the systems metabolic profile of centenarians, the paradigm of human healthy aging and longevity. Meanwhile, how to well characterize the system-level metabolic states in an organism of interest remains to be a major challenge in systems metabolism research. To address this challenge and better understand the metabolic mechanisms of healthy aging, we developed a method of genome-wide precision metabolic modeling (GPMM) which is able to quantitatively integrate transcriptome, proteome and kinetome data in predictive modeling of metabolic networks. Benchmarking analysis showed that GPMM successfully characterized metabolic reprogramming in the NCI-60 cancer cell lines; it dramatically improved the performance of the modeling with an R2 of 0.86 between the predicted and experimental measurements over the performance of existing methods. Using this approach, we examined the metabolic networks of a Chinese centenarian cohort and identified the elevated fatty acid oxidation (FAO) as the most significant metabolic feature in these long-lived individuals. Evidence from serum metabolomics supports this observation. Given that FAO declines with normal aging and is impaired in many age-related diseases, our study suggests that the elevated FAO has potential to be a novel signature of healthy aging of humans.

Keywords:  GPMM; aging; longevity; metabolic modeling; omics integration; systems biology

DOI:  https://doi.org/10.1111/acel.13595
Aging (Albany NY). 2022 Mar 27. undefined(undefined):

Targeting anxiety and senescence with senolytics.

Marco Raffaele, Manlio Vinciguerra.



Keywords:  anxyolitics; nociceptin receptors; senolytics

DOI:  https://doi.org/10.18632/aging.203985
Stem Cells. 2022 Mar 31. 40(3): 318-331

Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche.

Francesca Natale, Lucia Leone, Marco Rinaudo, Raimondo Sollazzo, Saviana Antonella Barbati, Francesco La Greca, Matteo Spinelli, Salvatore Fusco, Claudio Grassi.

  Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non-communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on insulin receptor substrate-1 (IRS-1)/ Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS-1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high-fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.

Keywords:  adult neurogenesis; ageing; extracellular vesicles; insulin resistance; neural stem cells; personalized medicine; senescence

DOI:  https://doi.org/10.1093/stmcls/sxab026
Aging Cell. 2022 Mar 27. e13596

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.

Ameya S Kulkarni, Sandra Aleksic, David M Berger, Felipe Sierra, George A Kuchel, Nir Barzilai.

  Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience-guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA-approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)-like study involving such candidate gerotherapeutics.

Keywords:  aging; clinical trials; drug repurposing; geroscience; preclinical studies

DOI:  https://doi.org/10.1111/acel.13596
J Oncol. 2022 ;2022 5705896

Prp19 Facilitated p21-Dependent Senescence of Hepatocellular Carcinoma Cells.

Jie Yin, Guang-Cong Zhang, Ying Fang, Xiang-Nan Yu, Tao-Tao Liu, Ling Dong, Xi-Zhong Shen.

Introduction: Evidence suggests that the role of senescence in the development of cancer is context-dependent. An orthologue of human pre-mRNA processing factor 19 (Prp19) attenuates the senescence of human endothelial cells. Prp19 has been reported to be involved in the progression of hepatocellular carcinoma (HCC). This work aims to investigate the effect of Prp19 on the senescence of HCC.
Materials and Methods: Senescence of L02 cells and HCC cells under different stimuli was detected through cell cycle analysis, SA-β-gal staining, and senescence associated secretory phenotype analysis. The relationship between Prp19 and senescence-related proteins was evaluated using real-time RT-PCR, western blot assay, and immunohistochemistry. Subcutaneous xenograft tumors in nude mice were used to evaluate the role of Prp19 on senescence in vivo. Data analysis was carried out using GraphPad Prism 6.
Results: Prp19 facilitated the senescence of L02 cells and HCC cells under different stresses. Prp19 positively modulated p21 expression in the mRNA level. Downregulation of Prp19 promoted the growth of subcutaneous xenograft tumors generated by HCC cell lines.
Conclusions: Prp19 may promote senescence of HCC cells via regulating p21 expression.

DOI: https://doi.org/10.1155/2022/5705896
Front Cell Dev Biol. 2022 ;10 810282

Advanced Oxidative Protein Products Drive Trophoblast Cells Into Senescence by Inhibiting the Autophagy: The Potential Implication of Preeclampsia.

Zhengjuan Li, Shuoshi Wang, Liping Li.

  Introduction: Advanced oxidation protein products (AOPPs), the novel marker of oxidative stress, have been found to be elevated in preeclampsia (PE). To date, the effect of AOPPs on the senescence of trophoblast cells is still unclear. In this study, we investigated whether AOPPs promoted the senescence of trophoblast cells and explored the underlying mechanisms of AOPPs-induced aging process which may facilitate the progression of PE. Methods: The trophoblast cell line HTR-8/SV neo cells were cultured in the presence of PBS, AOPPs, AOPPs plus an anti-oxidant N-acetyl-L-cysteine (NAC). In some experiments, cells were pre-treated with rapamycin (an activator of autophagy), 3-MA (an inhibitor of autophagy), or cyclic pifithrin-α (PFT-α, an antagonist of p53), and then treated with AOPPs. Cellular senescence was analyzed by measuring the levels of senescence-associated β-galactosidase (SA β-Gal), senescence-associated heterochromatin foci (SAHF), mitochondrial membrane potential (ΔΨm), and cell cycle. Cell autophagic flux was analyzed by measuring tandem fluorescence-tagged LC3 reporter (mCherry-EGFP-LC3). Levels of p53, phosphorylated p53 (p-p53), p21, BECN1, p62, p-mTOR and p-p70S6K were measured by western blot. Results: Treatment with AOPPs significantly increased the levels of SA β-Gal and SAHF, the percentage of cells in the G0/G1 phase, and decreased cell ΔΨm compared with the control group. Co-treatment with NAC and AOPPs significantly reversed AOPPs-induced senescence. Pre-treatment with rapamycin or 3-MA significantly inhibited or promoted AOPPs-induced senescence, respectively. In addition, administration of AOPPs significantly decreased the numbers of mCherry+EGFP+ autophagosomes and mCherry+EGFP- autolysosomes in cells compared with cells treated with PBS. Furthermore, AOPPs significantly increased the levels of proteins p-p53, p21, p-mTOR and p-p70S6K compared with the control group. Pre-treatment with rapamycin or PFT-α significantly down-regulated the levels of SA β-Gal, SAHF, p-p53, p21, autophagy related protein p62, the percentage of cells in the G0/G1 phase, and significantly up-regulated ΔΨm, autophagy related protein BECN1, autophagosomes and autolysosomes compared with cells only treated with AOPPs. Conclusion: AOPPs may induce trophoblast cell senescence by inhibiting the autophagy process in a p53/mTOR/p70S6K-dependent pathway.

Keywords:  AOPPs; autophagy; mTOR; oxidative Stress; p53; preeclampsia; senescence; trophoblast cells

DOI:  https://doi.org/10.3389/fcell.2022.810282
Ageing Res Rev. 2022 Mar 23. pii: S1568-1637(22)00052-6. [Epub ahead of print]77 101610

Noncoding RNAs in age-related cardiovascular diseases.

EU-CardioRNA COST Action CA17129

  Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the adult population worldwide and represent a severe economic burden and public health concern. The majority of human genes do not code for proteins. However, noncoding transcripts play important roles in ageing that significantly increases the risk for CVDs. Noncoding RNAs (ncRNAs) are critical regulators of multiple biological processes related to ageing such as oxidative stress, mitochondrial dysfunction and chronic inflammation. NcRNAs are also involved in pathophysiological developments within the cardiovascular system including arrhythmias, cardiac hypertrophy, fibrosis, myocardial infarction and heart failure. In this review article, we cover the roles of ncRNAs in cardiovascular ageing and disease as well as their potential therapeutic applications in CVDs.

Keywords:  Ageing; Cardiovascular disease; Inflammageing; Noncoding RNAs

DOI:  https://doi.org/10.1016/j.arr.2022.101610
Stem Cells. 2022 Mar 31. 40(3): 290-302

ROR2 Downregulation Activates the MSX2/NSUN2/p21 Regulatory Axis and Promotes Dental Pulp Stem Cell Senescence.

Xin He, Zhan Yang, Xiao-Yang Chu, Yun-Xia Li, Biao Zhu, Yan-Xia Huang, Wei Wang, Chun-Yan Gao, Xu Chen, Chun-Yan Zheng, Kai Yang, Dong-Liang Zhang.

  Cellular senescence severely limits the research and the application of dental pulp stem cells (DPSCs). A previous study conducted by our research group revealed a close implication of ROR2 in DPSC senescence, although the mechanism underlying the regulation of ROR2 in DPSCs remains poorly understood so far. In the present study, it was revealed that the expression of the ROR2-interacting transcription factor MSX2 was increased in aging DPSCs. It was demonstrated that the depletion of MSX2 inhibits the senescence of DPSCs and restores their self-renewal capacity, and the simultaneous overexpression of ROR2 enhanced this effect. Moreover, MSX2 knockdown suppressed the transcription of NOP2/Sun domain family member 2 (NSUN2), which regulates the expression of p21 by binding to and causing the 5-methylcytidine methylation of the 3'- untranslated region of p21 mRNA. Interestingly, ROR2 downregulation elevated the levels of MSX2 protein, and not the MSX2 mRNA expression, by reducing the phosphorylation level of MSX2 and inhibiting the RNF34-mediated MSX2 ubiquitination degradation. The results of the present study demonstrated the vital role of the ROR2/MSX2/NSUN2 axis in the regulation of DPSC senescence, thereby revealing a potential target for antagonizing DPSC aging.

Keywords:  MSX2; NSUN2; ROR2; dental pulp stem cell; senescence

DOI:  https://doi.org/10.1093/stmcls/sxab024
Aging Cell. 2022 Mar 31. e13600

Alzheimer-like tau accumulation in dentate gyrus mossy cells induces spatial cognitive deficits by disrupting multiple memory-related signaling and inhibiting local neural circuit.

Shihong Li, Qiuzhi Zhou, Enjie Liu, Huiyun Du, Nana Yu, Haitao Yu, Weijin Wang, Mengzhu Li, Ying Weng, Yang Gao, Guilin Pi, Xin Wang, Dan Ke, Jian-Zhi Wang.

  Abnormal tau accumulation and spatial memory loss constitute characteristic pathology and symptoms of Alzheimer disease (AD). Yet, the intrinsic connections and the mechanism between them are not fully understood. In the current study, we observed a prominent accumulation of the AD-like hyperphosphorylated and truncated tau (hTau N368) proteins in hippocampal dentate gyrus (DG) mossy cells of 3xTg-AD mice. Further investigation demonstrated that the ventral DG (vDG) mossy cell-specific overexpressing hTau for 3 months induced spatial cognitive deficits, while expressing hTau N368 for only 1 month caused remarkable spatial cognitive impairment with more prominent tau pathologies. By in vivo electrophysiological and optic fiber recording, we observed that the vDG mossy cell-specific overexpression of hTau N368 disrupted theta oscillations with local neural network inactivation in the dorsal DG subset, suggesting impairment of the ventral to dorsal neural circuit. The mossy cell-specific transcriptomic data revealed that multiple AD-associated signaling pathways were disrupted by hTau N368, including reduction of synapse-associated proteins, inhibition of AKT and activation of glycogen synthase kinase-3β. Importantly, chemogenetic activating mossy cells efficiently attenuated the hTau N368-induced spatial cognitive deficits. Together, our findings indicate that the mossy cell pathological tau accumulation could induce the AD-like spatial memory deficit by inhibiting the local neural network activity, which not only reveals new pathogenesis underlying the mossy cell-related spatial memory loss but also provides a mouse model of Mossy cell-specific hTau accumulation for drug development in AD and the related tauopathies.

Keywords:  Alzheimer's disease; hTau N368; hippocampus; mossy cell; spatial memory

DOI:  https://doi.org/10.1111/acel.13600
Nat Rev Cardiol. 2022 Mar 30.

Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets.

Mandy O J Grootaert, Martin R Bennett.

Sirtuins are NAD+-dependent deacetylase and deacylase enzymes that control important cellular processes, including DNA damage repair, cellular metabolism, mitochondrial function and inflammation. Consequently, mammalian sirtuins are regarded as crucial regulators of cellular function and organism healthspan. Sirtuin activity and NAD+ levels decrease with age in many tissues, and reduced sirtuin expression is associated with several cardiovascular diseases. By contrast, increased sirtuin expression and activity slows disease progression and improves cardiovascular function in preclinical models and delays various features of cellular ageing. The potential cardiometabolic benefits of sirtuins have resulted in clinical trials with sirtuin-modulating agents; although expectations are high, these drugs have not yet been proven to improve healthspan. In this Review, we examine the role of sirtuins in atherosclerosis, summarize advances in the development of compounds that activate or inhibit sirtuin activity and critically evaluate the therapeutic potential of these agents.

DOI: https://doi.org/10.1038/s41569-022-00685-x
Cell Death Differ. 2022 Mar 28.

Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration.

Ming Zou, Qin Ke, Qian Nie, Ruili Qi, Xingfei Zhu, Wei Liu, Xuebin Hu, Qian Sun, Jia-Ling Fu, Xiangcheng Tang, Yizhi Liu, David Wan-Cheng Li, Lili Gong.

Atrophic ("dry") form of age-related macular degeneration (AMD) is a leading cause of vision loss characterized by macular retinal pigment epithelium (RPE) and the ensuing photoreceptor degeneration. cGAS-STING signaling is a key cytosolic DNA sensor system in innate immunity and have recently been shown promotes RPE degeneration. However, expression regulation and therapeutic potential of cGAS and STING are not explored in retina under dry AMD pathogenic conditions. Our analysis shows upregulated STING RNA and increased chromatin accessibility around cGAS and STING promoters in macular retinas from dry AMD patients. cGAS-STING activation was detected in oxidative stress-induced mouse retina degeneration, accompanied with cytosolic leakage of damaged DNA in photoreceptors. Pharmaceutical or genetic approaches indicates STING promotes retina inflammation and degeneration upon oxidative damage. Drug screening reveals that BRD4 inhibitor JQ1 reduces cGAS-STING activation, inflammation and photoreceptor degeneration in the injured retina. BRD4 inhibition epigenetically suppresses STING transcription, and promotes autophagy-dependent cytosolic DNA clearance. Together, our results show that activation of cGAS-STING in retina may present pivotal innate immunity response in GA pathogenesis, whereas inhibition of cGAS-STING signaling by JQ1 could serve as a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41418-022-00967-4
Trends Genet. 2022 Mar 25. pii: S0168-9525(22)00037-3. [Epub ahead of print]

The p53 network: cellular and systemic DNA damage responses in cancer and aging.

Pavana Lakshmi Vaddavalli, Björn Schumacher.

  The tumor protein TP53 gene, encoding the cellular tumor antigen p53, is the single most frequently mutated gene in human cancers. p53 plays a central role in responding to DNA damage and determines the outcome of the DNA damage checkpoint response by regulating cell cycle arrest and apoptosis. As a consequence of this function, dysfunctional p53 results in cells that, despite a damaged genome, continue to proliferate thus fueling malignant transformation. New insights have recently been gained into the complexity of the p53 regulation of the DNA damage response (DDR) and how it impacts a wide variety of cellular processes. In addition to cell-autonomous signaling mechanisms, non-cell-autonomous regulatory inputs influence p53 activity, which in turn can have systemic consequences on the organism. New inroads have also been made toward therapeutic targeting of p53 that for a long time has been anticipated.

Keywords:  DNA damage; aging; cancer; p53; tumor suppression

DOI:  https://doi.org/10.1016/j.tig.2022.02.010
Front Mol Neurosci. 2022 ;15 844193

Roles of Long Non-coding RNAs in the Development of Aging-Related Neurodegenerative Diseases.

Yu-Qing Ni, Hui Xu, You-Shuo Liu.

  Aging-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), are gradually becoming the primary burden of society and cause significant health-care concerns. Aging is a critical independent risk factor for neurodegenerative diseases. The pathological alterations of neurodegenerative diseases are tightly associated with mitochondrial dysfunction, inflammation, and oxidative stress, which in turn stimulates the further progression of neurodegenerative diseases. Given the potential research value, lncRNAs have attracted considerable attention. LncRNAs play complex and dynamic roles in multiple signal transduction axis of neurodegeneration. Emerging evidence indicates that lncRNAs exert crucial regulatory effects in the initiation and development of aging-related neurodegenerative diseases. This review compiles the underlying pathological mechanisms of aging and related neurodegenerative diseases. Besides, we discuss the roles of lncRNAs in aging. In addition, the crosstalk and network of lncRNAs in neurodegenerative diseases are also explored.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; ageing; amyotrophic lateral sclerosis; long non-coding RNAs; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fnmol.2022.844193
Mech Ageing Dev. 2022 Mar 25. pii: S0047-6374(22)00050-1. [Epub ahead of print]204 111668

Trimethylamine N-oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model.

María Lanz, Manuel H Janeiro, Fermin I Milagro, Elena Puerta, Iziar A Ludwig, Antonio Pineda-Lucena, María J Ramírez, Maite Solas.

  It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.

Keywords:  DMB; Gut dysbiosis; Inflammation; Microbiota; Neurodegeneration

DOI:  https://doi.org/10.1016/j.mad.2022.111668
Ageing Res Rev. 2022 Mar 26. pii: S1568-1637(22)00057-5. [Epub ahead of print] 101615

Oxysterols are potential physiological regulators of ageing.

Philippe de Medina, Sandrine Silvente-Poirot, Marc Poirot.

  Delaying and even reversing ageing is a major public health challenge with a tremendous potential to postpone a plethora of diseases including cancer, metabolic syndromes and neurodegenerative disorders. A better understanding of ageing as well as the development of innovative anti-ageing strategies are therefore an increasingly important field of research. Several biological processes including inflammation, proteostasis, epigenetic, oxidative stress, stem cell exhaustion, senescence and stress adaptive response have been reported for their key role in ageing. In this review, we describe the relationships that have been established between cholesterol homeostasis, in particular at the level of oxysterols, and ageing. Initially considered as harmful pro-inflammatory and cytotoxic metabolites, oxysterols are currently emerging as an expanding family of fine regulators of various biological processes involved in ageing. Indeed, depending of their chemical structure and their concentration, oxysterols exhibit deleterious or beneficial effects on inflammation, oxidative stress and cell survival. In addition, stem cell differentiation, epigenetics, cellular senescence and proteostasis are also modulated by oxysterols. Altogether, these data support the fact that ageing is influenced by an oxysterol profile. Further studies are thus required to explore more deeply the impact of the "oxysterome" on ageing and therefore this cholesterol metabolic pathway constitutes a promising target for future anti-ageing interventions.

Keywords:  ageing; cholesterol homeostasis; metabolism; oxysterome; stress adaptive response

DOI:  https://doi.org/10.1016/j.arr.2022.101615
Proc Natl Acad Sci U S A. 2022 Apr 05. 119(14): e2121133119

Protective role of chaperone-mediated autophagy against atherosclerosis.

Julio Madrigal-Matute, Jenny de Bruijn, Kim van Kuijk, Dario F Riascos-Bernal, Antonio Diaz, Inmaculada Tasset, Adrián Martín-Segura, Marion J J Gijbels, Bianca Sander, Susmita Kaushik, Erik A L Biessen, Simoni Tiano, Mathieu Bourdenx, Gregory J Krause, Ian McCracken, Andrew H Baker, Han Jin, Nicholas E S Sibinga, Jose Javier Bravo-Cordero, Fernando Macian, Rajat Singh, Patrick C N Rensen, Jimmy F P Berbée, Gerard Pasterkamp, Judith C Sluimer, Ana Maria Cuervo.

  Significance Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to proatherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression.

Keywords:  atherosclerotic plaques; lipid challenge; lysosomes; proteolysis; vascular disease

DOI:  https://doi.org/10.1073/pnas.2121133119
Brain Commun. 2022 ;4(2): fcac036

Ageing is associated with maladaptive immune response and worse outcome after traumatic brain injury.

Federico Moro, Francesca Pischiutta, Anaïs Portet, Edward J Needham, Emma J Norton, John R Ferdinand, Gloria Vegliante, Eliana Sammali, Rosaria Pascente, Enrico Caruso, Edoardo Micotti, Daniele Tolomeo, Rafael di Marco Barros, Erik Fraunberger, Kevin K W Wang, Michael J Esser, David K Menon, Menna R Clatworthy, Elisa R Zanier.

  Traumatic brain injury is increasingly common in older individuals. Older age is one of the strongest predictors for poor prognosis after brain trauma, a phenomenon driven by the presence of extra-cranial comorbidities as well as pre-existent pathologies associated with cognitive impairment and brain volume loss (such as cerebrovascular disease or age-related neurodegeneration). Furthermore, ageing is associated with a dysregulated immune response, which includes attenuated responses to infection and vaccination, and a failure to resolve inflammation leading to chronic inflammatory states. In traumatic brain injury, where the immune response is imperative for the clearance of cellular debris and survey of the injured milieu, an appropriate self-limiting response is vital to promote recovery. Currently, our understanding of age-related factors that contribute to the outcome is limited; but a more complete understanding is essential for the development of tailored therapeutic strategies to mitigate the consequences of traumatic brain injury. Here we show greater functional deficits, white matter abnormalities and worse long-term outcomes in aged compared with young C57BL/6J mice after either moderate or severe traumatic brain injury. These effects are associated with altered systemic, meningeal and brain tissue immune response. Importantly, the impaired acute systemic immune response in the mice was similar to the findings observed in our clinical cohort. Traumatic brain-injured patient cohort over 70 years of age showed lower monocyte and lymphocyte counts compared with those under 45 years. In mice, traumatic brain injury was associated with alterations in peripheral immune subsets, which differed in aged compared with adult mice. There was a significant increase in transcription of immune and inflammatory genes in the meninges post-traumatic brain injury, including monocyte/leucocyte-recruiting chemokines. Immune cells were recruited to the region of the dural injury, with a significantly higher number of CD11b+ myeloid cells in aged compared with the adult mice. In brain tissue, when compared with the young adult mice, we observed a more pronounced and widespread reactive astrogliosis 1 month after trauma in aged mice, sustained by an early and persistent induction of proinflammatory astrocytic state. These findings provide important insights regarding age-related exacerbation of neurological damage after brain trauma.

Keywords:  ageing; meninges; neuroinflammation; reactive astrogliosis; traumatic brain injury

DOI:  https://doi.org/10.1093/braincomms/fcac036
Aging Cell. 2022 Mar 30. e13593

Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription.

De-Juan Yuan, Guang Yang, Wei Wu, Qi-Fa Li, De-En Xu, Michael Ntim, Chun-Yan Jiang, Ji-Chuan Liu, Yue Zhang, Ying-Zi Wang, Dan-Dan Zhu, Supratik Kundu, Ai-Ping Li, Zhi-Cheng Xiao, Quan-Hong Ma, Shao Li.

  Aberrant increases in neuronal network excitability may contribute to cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability of neurons are not fully understood. Voltage-gated sodium channels (VGSC or Nav), which are involved in the formation of excitable cell's action potential and can directly influence the excitability of neural networks, have been implicated in AD-related abnormal neuronal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we have shown that the reduction of VGSC α-subunit Nav1.6 (by injecting adeno-associated virus (AAV) with short hairpin RNA (shRNA) into the hippocampus) rescues cognitive impairments and attenuates synaptic deficits in APP/PS1 transgenic mice. Concurrently, amyloid plaques in the hippocampus and levels of soluble Aβ are significantly reduced. Interfering with Nav1.6 reduces the transcription level of β-site APP-cleaving enzyme 1 (BACE1), which is Aβ-dependent. In the presence of Aβ oligomers, knockdown of Nav1.6 reduces intracellular calcium overload by suppressing reverse sodium-calcium exchange channel, consequently increasing inactive NFAT1 (the nuclear factor of activated T cells) levels and thus reducing BACE1 transcription. This mechanism leads to a reduction in the levels of Aβ in APP/PS1 transgenic mice, alleviates synaptic loss, improves learning and memory disorders in APP/PS1 mice after downregulating Nav1.6 in the hippocampus. Our study offers a new potential therapeutic strategy to counteract hippocampal hyperexcitability and subsequently rescue cognitive deficits in AD by selective blockade of Nav1.6 overexpression and/or hyperactivity.

Keywords:  Alzheimer's disease; BACE1; NFAT1; Nav1.6 sodium channel; amyloid-β; hyperexcitability

DOI:  https://doi.org/10.1111/acel.13593
Aging (Albany NY). 2022 Mar 31. 14(undefined):

E-cadherin deficiency promotes prostate macrophage inflammation and bladder overactivity in aged male mice.

Laura E Pascal, Taro Igarashi, Shinsuke Mizoguchi, Wei Chen, Lora H Rigatti, Caroline G Madigan, Rajiv Dhir, Wade Bushman, Donald B DeFranco, Naoki Yoshimura, Zhou Wang.

  Decreased E-cadherin immunostaining is frequently observed in benign prostatic hyperplasia (BPH) and was recently correlated with increased inflammation in aging prostate. Homozygous E-cadherin deletion in the murine prostate results in prostate inflammation and bladder overactivity at 6 months of age. However, this model is limited in that while E-cadherin is significantly reduced in BPH, it is not completely lost; BPH is also strongly associated with advanced age and is infrequent in young men. Here, we examined the functional consequences of aging in male mice with prostate luminal epithelial cell-specific E-cadherin heterozygosity. In control mice, aging alone resulted in an increase in prostate inflammation and changes in bladder voiding function indicative of bladder underactivity. At 24 months of age, mice with prostate-specific Cre-mediated heterozygous deletion of E-cadherin induced at 7 weeks of age developed additional prostatic defects, particularly increased macrophage inflammation and stromal proliferation, and bladder overactivity compared to age-matched control mice, which are similar to BPH/LUTS in that the phenotype is slow-progressing and age-dependent. These findings suggest that decreased E-cadherin may promote macrophage inflammation and fibrosis in the prostate and subsequent bladder overactivity in aging men, promoting the development and progression of BPH/LUTS.

Keywords:  BPH; Cdh1; E-cadherin; LUTS; aging; bladder overactivity; prostatic inflammation

DOI:  https://doi.org/10.18632/aging.203994