bims-senagi 2021-08-01 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–08–01
39 papers selected by
Maria Grazia Vizioli, Mayo Clinic

Dissecting primary and secondary senescence to enable new senotherapeutic strategies.
Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis.
Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span.
The Cancer SENESCopedia: A delineation of cancer cell senescence.
Senolytic treatment modulates decidualization in human endometrial stromal cells.
All cells are created equal in the sight of autophagy: selective autophagy maintains homeostasis in senescent cells.
Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis.
Trends in Natural Nutrients for Oxidative Stress and Cell Senescence.
Gasotransmitter CO Attenuates Bleomycin-Induced Fibroblast Senescence via Induction of Stress Granule Formation.
Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation.
Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm.
Aging increases senescence, calcium signaling, and extracellular matrix deposition in human airway smooth muscle.
cGAS-STING pathway: post-translational modifications and functions in sterile inflammatory diseases.
Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases.
The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging.
Olfactory dysfunction in aging and neurodegenerative diseases.
The role of mTOR in age-related diseases.
Decreased antiviral immune response within the central nervous system of aged mice is associated with increased lethality of West Nile virus encephalitis.
The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs.
HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity.
Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis.
Cellular senescence or stemness: hypoxia flips the coin.
LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells.
Features of age-related response to sleep deprivation: in vivo experimental studies.
Telomere associated gene expression as well as TERT protein level and telomerase activity are altered in the ovarian follicles of aged mice.
TFAM-deficient mouse skin fibroblasts: an ex vivo model of mitochondrial dysfunction.
Nampt affects mitochondrial function in aged oocytes by mediating the downstream effector FoxO3a.
Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis.
Nrf2 deficiency decreases NADPH from impaired IDH shuttle and pentose phosphate pathway in retinal pigmented epithelial cells to magnify oxidative stress-induced mitochondrial dysfunction.
Transcriptome features of striated muscle aging and predictability of protein level changes.
Age-related neuroinflammation and pathology in the locus coeruleus and hippocampus: beta-adrenergic antagonists exacerbate impairment of learning and memory in aged mice.
Anti-aging properties of phytoconstituents and phyto-nanoemulsions and their application in managing aging-related diseases.
Rewiring of the ubiquitinated proteome determines ageing in C. elegans.
SGLT2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body-induced NRF2 activation.
Naïve T Cell Quiescence in Immune Aging.
The trans-omics landscape of COVID-19.
A Tale of Two States: Pluripotency Regulation of Telomeres.
Telomere length and metabolic syndrome traits: A Mendelian randomisation study.
Vaccination as a preventative measure contributing to immune fitness.

Ageing Res Rev. 2021 Jul 21. pii: S1568-1637(21)00159-8. [Epub ahead of print]70 101412

Dissecting primary and secondary senescence to enable new senotherapeutic strategies.

Tesfahun Dessale Admasu, Michael Rae, Alexandra Stolzing.

  Cellular senescence is a state of stable cell cycle arrest that is known to be elicited in response to different stresses or forms of damage. Senescence limits the replication of old, damaged, and precancerous cells in the short-term but is implicated in diseases and debilities of aging due to loss of regenerative reserve and secretion of a complex combination of factors called the senescence-associated secretory phenotype (SASP). More recently, investigators have discovered that senescent cells induced by these methods (what we term "primary senescent cells") are also capable of inducing other non-senescent cells to undergo senescence - a phenomenon we call "secondary senescence." Secondary senescence has been demonstrated to occur via two broad types of mechanisms. First, factors in the SASP have been shown to be involved in spreading senescence; we call this phenomenon "paracrine senescence." Second, primary senescent cells can induce senescence via an additional group of mechanisms involving cell-to-cell contacts of different types; we term this phenomenon "juxtacrine senescence." "Secondary senescence" in our definition is thus the overarching term for both paracrine and juxtacrine senescence together. By allowing cells that are inherently small in number and incapable of replication to increase in number and possibly spread to anatomically distant locations, secondary senescence allows an initially small number of senescent cells to contribute further to age-related pathologies. We propose that understanding how primary and secondary senescent cells differ from each other and the mechanisms of their spread will enable the development of new rejuvenation therapies to target different senescent cell populations and interrupt their spread, extending human health- and potentially lifespan.

Keywords:  Aging; Bystander; Juxtacrine; Paracrine; SASP; Secondary senescence; Senescence

DOI:  https://doi.org/10.1016/j.arr.2021.101412
Nat Commun. 2021 07 27. 12(1): 4559

Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis.

Riccardo Biavasco, Emanuele Lettera, Kety Giannetti, Diego Gilioli, Stefano Beretta, Anastasia Conti, Serena Scala, Daniela Cesana, Pierangela Gallina, Margherita Norelli, Luca Basso-Ricci, Attilio Bondanza, Giulio Cavalli, Maurilio Ponzoni, Lorenzo Dagna, Claudio Doglioni, Alessandro Aiuti, Ivan Merelli, Raffaella Di Micco, Eugenio Montini.

Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (BRAFV600E). All mice transplanted with BRAFV600E-expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. At the basis of this aggressive phenotype, we uncover the engagement of a senescence program, characterized by DNA damage response activation and a senescence-associated secretory phenotype, which affects also non-mutated bystander cells. Mechanistically, we identify TNFα as a key determinant of paracrine senescence and myeloid-restricted hematopoiesis and show that its inhibition dampens inflammation, delays disease onset and rescues hematopoietic defects in bystander cells. Our work establishes that senescence in the human hematopoietic system links oncogene-activation to the systemic inflammation observed in histiocytic neoplasms.

DOI: https://doi.org/10.1038/s41467-021-24876-1
Science. 2021 07 30. pii: eabc8479. [Epub ahead of print]373(6554):

Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span.

M Grunewald, S Kumar, H Sharife, E Volinsky, A Gileles-Hillel, T Licht, A Permyakova, L Hinden, S Azar, Y Friedmann, P Kupetz, R Tzuberi, A Anisimov, K Alitalo, M Horwitz, S Leebhoff, O Z Khoma, R Hlushchuk, V Djonov, R Abramovitch, J Tam, E Keshet.

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, "inflammaging" (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

DOI: https://doi.org/10.1126/science.abc8479
Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00858-5. [Epub ahead of print]36(4): 109441

The Cancer SENESCopedia: A delineation of cancer cell senescence.

Fleur Jochems, Bram Thijssen, Giulia De Conti, Robin Jansen, Ziva Pogacar, Kelvin Groot, Liqin Wang, Arnout Schepers, Cun Wang, Haojie Jin, Roderick L Beijersbergen, Rodrigo Leite de Oliveira, Lodewyk F A Wessels, René Bernards.

  Cellular senescence is characterized as a stable proliferation arrest that can be triggered by multiple stresses. Most knowledge about senescent cells is obtained from studies in primary cells. However, senescence features may be different in cancer cells, since the pathways that are involved in senescence induction are often deregulated in cancer. We report here a comprehensive analysis of the transcriptome and senolytic responses in a panel of 13 cancer cell lines rendered senescent by two distinct compounds. We show that in cancer cells, the response to senolytic agents and the composition of the senescence-associated secretory phenotype are more influenced by the cell of origin than by the senescence trigger. Using machine learning, we establish the SENCAN gene expression classifier for the detection of senescence in cancer cell samples. The expression profiles and senescence classifier are available as an interactive online Cancer SENESCopedia.

Keywords:  ABT-263; SASP; SENCAN; SENESCopedia; cancer; cell cycle; gene expression classifier; senescence; senolytics; transcriptome profiling

DOI:  https://doi.org/10.1016/j.celrep.2021.109441
Biochem Biophys Res Commun. 2021 Jul 27. pii: S0006-291X(21)01111-6. [Epub ahead of print]571 174-180

Senolytic treatment modulates decidualization in human endometrial stromal cells.

Kazuya Kusama, Naoya Yamauchi, Kanoko Yoshida, Mana Azumi, Mikihiro Yoshie, Kazuhiro Tamura.

  Decidualization - the differentiation of endometrial stromal cells (ESCs) into decidual cells - is a crucial step for successful embryo implantation and placentation that is initiated in the secretory phase of the menstrual cycle. During decidualization, ESCs undergo proliferation arrest and secrete inflammatory mediators, including senescence-associated secretory phenotype (SASP). Although several senolytic agents improve age-related diseases, their effects on cellular senescence in decidualizing ESCs has not been explored. To do this, we treated decidualized ESCs with the senolytic agents Quercetin (Que), Dasatinib (Das), and BPTES. Que decreased the number of senescence-associated β-galactosidase (SA-β-Gal) positive cells and expression of senescence markers in ESCs treated with the decidual stimulus (dibutyryl-cAMP plus progesterone: DP). Concomitantly, Que markedly increased the expression of the decidualization markers IGFBP1, PRL, and FOXO1, in decidualizing ESCs. Similar to Que, Das also stimulated decidualization. Treatment with a combination of Que and Das synergistically increased the expression of decidualization markers and senescence markers compared with treatment with Que or Das alone. However, BPTES did not enhance the expression of decidualization markers. These results imply that treatment with Que and/or Das can remove senescent decidual cells and enhance the decidualization of the rest of ESCs. Thus, senolytic modulation of abnormal ESC decidualization could alleviate infertility caused by dysfunctions of endometrial receptivity and embryo implantation.

Keywords:  Cellular senescence; Decidualization; Endometrial stromal cell; Quercetin; Senolysis

DOI:  https://doi.org/10.1016/j.bbrc.2021.07.075
Autophagy. 2021 Jul 27. 1-2

All cells are created equal in the sight of autophagy: selective autophagy maintains homeostasis in senescent cells.

Jaejin Kim, Yeonghyeon Lee, Taerang Jeon, Mi-Sung Kim, Chanhee Kang.

  Macroautophagy/autophagy is a sophisticated quality control program that limits cellular damage and maintains homeostasis, being an essential part of several lifespan-promoting interventions. However, autophagy is also necessary for full establishment of cellular senescence, a causal factor for many age-related diseases and aging. What lies ahead of us to unravel such a paradoxical role of autophagy in senescence is to identify specific targets degraded by autophagy during senescence and determine their importance in the senescence regulatory network. Recently, we developed the "Selective autophagy substrates Identification Platform (SIP)" to advance these goals, providing a rich set of autophagy substrate proteins involved in senescence. Our study demonstrated that selective autophagy coordinates the stress support networks in senescent cells by degrading multiple regulatory components, echoing its homeostatic roles in normal cells. Targeting this type of selective autophagy might provide a unique opportunity to develop non-senescence addiction-based therapeutic strategies for senotherapy by disturbing the homeostatic state of senescent cells.

Keywords:  Autophagy interactome; cellular senescence; inflammation; oxidative stress; proteostasis; regulated protein stability; selective autophagy; stress support networks

DOI:  https://doi.org/10.1080/15548627.2021.1953848
Clin Sci (Lond). 2021 Jul 28. pii: CS20210447. [Epub ahead of print]

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis.

Wangqiu Gong, Congwei Luo, FenFen Peng, Jing Xiao, Yiqun Zeng, Bohui Yin, Xiaowen Chen, Shuting Li, Xiaoyang He, Yanxia Liu, Huihui Cao, Jiangping Xu, Haibo Long.

  Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWltch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly upregulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished TGF-β1-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs cells or normal kidneys increased p16INK4a, p19ARF and p21 expression and senescence-associated β-galactosidase activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by siRNA-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT- 263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.

Keywords:  Brahma-related gene 1; Wnt/β-catenin; autophagy; cellular senescence; renal fibrosis

DOI:  https://doi.org/10.1042/CS20210447
Oxid Med Cell Longev. 2021 ;2021 7501424

Trends in Natural Nutrients for Oxidative Stress and Cell Senescence.

Navid Omidifar, Mohsen Moghadami, Seyyed Mojtaba Mousavi, Seyyed Alireza Hashemi, Ahmad Gholami, Mansoureh Shokripour, Zahra Sohrabi.

Due to the increase in the aged population and increased life expectancy, the underlying mechanisms involved in the aging process and cell senescence and the ways for modulating these processes in age-related diseases become important. One of the main mechanisms involved in aging and cell senescence, especially in the diseases related to aging, is the oxidative stress process and the following inflammation. Hence, the effects of antioxidants are highlighted in the literature due to their beneficial impacts on inhibiting telomere shortening or DNA damage and other processes related to aging and cell senescence in age-related diseases. Dietary components, foods, and dietary patterns rich in antioxidants can modulate the aging process and delay the progression of some chronic diseases such as cardiovascular diseases, diabetes, and Alzheimer's disease. Foods high in polyphenols, vitamin C, or carotenoids, olive oil, seeds, nuts, legumes, dietary supplements such as CoQ10, and some other dietary factors are the most important nutritional sources that have high antioxidant contents which can positively affect cell senescence and disease progression. Plant dietary patterns including Mediterranean diets can also inhibit telomere shortening following oxidative damages, and this can delay cell aging and senescence in age-related diseases. Further, olive oil can inhibit protein aggregation in Alzheimer's disease. It can be concluded that nutrition can delay the process of cell senescence in age-related diseases via inhibiting oxidative and inflammatory pathways. However, more studies are needed to better clarify the underlying mechanisms of nutrition and dietary components on cell senescence, aging, and disease progression, especially those related to age.

DOI: https://doi.org/10.1155/2021/7501424
Oxid Med Cell Longev. 2021 ;2021 9926284

Gasotransmitter CO Attenuates Bleomycin-Induced Fibroblast Senescence via Induction of Stress Granule Formation.

Yingqing Chen, Feng Jiang, Guangyao Kong, Shuo Yuan, Yuying Cao, Qinggao Zhang, Qianqian Wang, Liping Liu.

Cellular senescence is recognized as a phenomenon wherein a proliferative cell undergoes a permanent growth arrest. The accumulation of senescent cells over time can become harmful and result in diseases and physiological decline. Plasminogen activator inhibitor (PAI-1) is considered as a critical marker and mediator of cellular senescence. The formation of stress granules (SGs) could prevent senescence through the sequestration of PAI-1, and we previously suggested that exogenous carbon monoxide (CO) could induce SG assembly via integrated stress response (ISR). Although CO is known to possess anti-inflammatory, antioxidative, and antiapoptotic properties, whether it exerts antisenescent effect is still not well defined. Here, to address whether CO-induced SGs could protect against cellular senescence, we first treated lung fibroblasts with bleomycin (BLM) to establish DNA damage-induced cellular senescence, and observed a significant increase of several hallmarks of senescence through SA-β-gal staining, immunofluorescence, qRT-PCR, and Western blot assay. However, pre- and posttreatment of CO could remarkably attenuate these senescent phenotypes. According to our immunofluorescence results, CO-induced SGs could inhibit BLM-induced cellular senescence via sequestration of PAI-1, while it was abolished after the cotreatment of ISR inhibitor (ISRIB) due to the inhibition of SG assembly. Overall, our results proposed a novel role of CO in suppressing bleomycin-induced lung fibroblast senescence through the assembly of SGs.

DOI: https://doi.org/10.1155/2021/9926284
Aging (Albany NY). 2021 Jul 30. 13(undefined):

Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation.

Wei Sun, Xiaoyan Jing, Xiaoyu Yang, Hui Huang, Qun Luo, Shu Xia, Ping Wang, Na Wang, Qian Zhang, Jian Guo, Zuojun Xu.

  Idiopathic pulmonary fibrosis (IPF) mainly occurs in elderly people over the age of sixty. IPF pathogenesis is associated with alveolar epithelial cells (AECs) senescence. Activation of PI3K/AKT signaling induced by insulin-like growth factor 1 (IGF1) participates in AEC senescence and IPF by releasing CTGF, TGF-β1, and MMP9. Our previous study demonstrated that core fucosylation (CF) modification, catalyzed by a specific core fucosyltransferase (FUT8) can regulate the activation of multiple signaling pathways, and inhibiting CF can alleviate pulmonary fibrosis in mice induced by bleomycin. However, whether CF is involved in IGF1-mediated AEC senescence in IPF remains unclear. In this study, we found that the IGF1/PI3K/AKT signaling pathway was activated in IPF lung tissue. Meanwhile, CF was present in senescent AECs. We also showed that IGF1 could induce AECs senescence with enhanced CF in vivo and in vitro. Inhibiting CF alleviated AECs senescence and pulmonary fibrosis induced by IGF1. In addition, activation of IGF1/PI3K/AKT signaling depends on CF. In conclusion, this study confirmed that CF is an important target regulating the IGF1 signaling pathway in AEC senescence and IPF, which might be a candidate target to treat IPF in the future.

Keywords:  IGF-1; IPF; aging; alveolar epithelial cell; core fucosylation

DOI:  https://doi.org/10.18632/aging.203335
Proc Natl Acad Sci U S A. 2021 Aug 03. pii: e2107898118. [Epub ahead of print]118(31):

Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm.

Chongyang Zhang, Hongmei Zhao, Yujun Cai, Jian Xiong, Amy Mohan, Danfei Lou, Hangchuan Shi, Yishuai Zhang, Xiaochun Long, Jing Wang, Chen Yan.

  Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated β-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.

Keywords:  abdominal aortic aneurysm; phosphodiesterase; senescence; vascular smooth muscle cell

DOI:  https://doi.org/10.1073/pnas.2107898118
PLoS One. 2021 ;16(7): e0254710

Aging increases senescence, calcium signaling, and extracellular matrix deposition in human airway smooth muscle.

Sarah A Wicher, Benjamin B Roos, Jacob J Teske, Yun Hua Fang, Christina Pabelick, Y S Prakash.

Lung function declines as people age and their lungs become stiffer. With an increasing elderly population, understanding mechanisms that contribute to these structural and functional changes in the aging lung is important. Part of the aging process is characterized by thicker, more fibrotic airways, and senile emphysema caused by changes in lung parenchyma. There is also senescence, which occurs throughout the body with aging. Here, using human airway smooth muscle (ASM) cells from patients in different age groups, we explored senescence pathways and changes in intracellular calcium signaling and extracellular matrix (ECM) deposition to elucidate potential mechanisms by which aging leads to thicker and stiffer lungs. Senescent markers p21, γH2AX, and β-gal, and some senescence-associated secretory proteins (SASP) increased with aging, as shown by staining and biochemical analyses. Agonist-induced intracellular Ca2+ responses, measured using fura-2 loaded cells and fluorescence imaging, increased with age. However, biochemical analysis showed that expression of the following markers decreased with age: M3 muscarinic receptor, TRPC3, Orai1, STIM1, SERCA2, MMP2 and MMP9. In contrast, collagen III, and fibronectin deposition increased with age. These data show that senescence increases in the aging airways that is associated with a stiffer but surprisingly greater intracellular calcium signaling as a marker for contractility. ASM senescence may enhance fibrosis in a feed forward loop promoting remodeling and altered calcium storage and buffering.

DOI: https://doi.org/10.1371/journal.pone.0254710
FEBS J. 2021 Jul 26.

cGAS-STING pathway: post-translational modifications and functions in sterile inflammatory diseases.

Ze Hong, Tianchi Ma, Xing Liu, Chen Wang.

  Cytoplasmic microbial and host aberrant DNAs act as danger signals and trigger host immune responses. Upon recognition, the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) catalyzes the production of a second messenger 2'3'-cGAMP, which activates endoplasmic reticulum (ER)-associated stimulator of interferon genes (STING) and ultimately leads to the induction of type I interferons and inflammatory genes that collectively initiate host immune defense against microbial invasion. Inappropriate activation or suppression of this signaling pathway has been implicated in the development of some autoimmune diseases, sterile inflammation and cancers. In this review, we describe how the activity of cGAS and STING is regulated by host post-translational modifications and summarize the recent advances of cell-specific cGAS-STING activation and its association in sterile inflammatory diseases. We also discuss key outstanding questions in the field, including how our knowledge of cGAS-STING pathway could be translated into clinical applications.

Keywords:  STING; autoimmune disease; cGAS; post translational modification; sterile inflammatory disease

DOI:  https://doi.org/10.1111/febs.16137
Ageing Res Rev. 2021 Jul 26. pii: S1568-1637(21)00161-6. [Epub ahead of print] 101414

Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases.

Doortje W Dekens, Ulrich L M Eisel, Leonie Gouweleeuw, Regien G Schoemaker, Peter P De Deyn, Petrus J W Naudé.

  Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases.

Keywords:  Chronic inflammation; Inflammageing; Lifestyle; Neurodegenerative disease; Neuroinflammation; Neutrophil gelatinase-associated lipocalin (NGAL)

DOI:  https://doi.org/10.1016/j.arr.2021.101414
Cell Death Dis. 2021 Jul 27. 12(8): 744

The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging.

Zhong-Xin Jiang, Yi-Ning Wang, Zi-Yuan Li, Zhi-Hui Dai, Yi He, Kun Chu, Jia-Yi Gu, Yi-Xuan Ji, Ning-Xia Sun, Fu Yang, Wen Li.

Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3'UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.

DOI: https://doi.org/10.1038/s41419-021-04016-9
Ageing Res Rev. 2021 Jul 26. pii: S1568-1637(21)00163-X. [Epub ahead of print] 101416

Olfactory dysfunction in aging and neurodegenerative diseases.

Xiuli Dan, Noah Wechter, Samuel Gray, Joy G Mohanty, Deborah L Croteau, Vilhelm A Bohr.

  Alterations in olfactory functions are proposed to be early biomarkers for neurodegeneration. Many neurodegenerative diseases are age-related, including two of the most common, Parkinson's disease (PD) and Alzheimer's disease (AD). The establishment of biomarkers that promote early risk identification is critical for the implementation of early treatment to postpone or avert pathological development. Olfactory dysfunction (OD) is seen in 90% of early-stage PD patients and 85% of patients with early-stage AD, which makes it an attractive biomarker for early diagnosis of these diseases. Here, we systematically review widely applied smelling tests available for humans and some animal models and the relationships between OD and normal aging, PD, AD, and other conditions. The utility of OD as a biomarker for neurodegenerative disease diagnosis and future research directions are also discussed.

Keywords:  Alzheimer’s disease; Parkinson’s disease; aging; neurodegeneration; olfactory dysfunction

DOI:  https://doi.org/10.1016/j.arr.2021.101416
J Enzyme Inhib Med Chem. 2021 Dec;36(1): 1679-1693

The role of mTOR in age-related diseases.

Zofia Chrienova, Eugenie Nepovimova, Kamil Kuca.

  The ageing population is becoming a significant socio-economic issue. To address the expanding health gap, it is important to deepen our understanding of the mechanisms underlying ageing in various organisms at the single-cell level. The discovery of the antifungal, immunosuppressive, and anticancer drug rapamycin, which possesses the ability to extend the lifespan of several species, has prompted extensive research in the areas of cell metabolic regulation, development, and senescence. At the centre of this research is the mTOR pathway, with key roles in cell growth, proteosynthesis, ribosomal biogenesis, transcriptional regulation, glucose and lipid metabolism, and autophagy. Recently, it has become obvious that mTOR dysregulation is involved in several age-related diseases, such as cancer, neurodegenerative diseases, and type 2 diabetes mellitus. Additionally, mTOR hyperactivation affects the process of ageing per se. In this review, we provide an overview of recent insights into the mTOR signalling pathway, including its regulation and its influence on various hallmarks of ageing at the cellular level.

Keywords:  Ageing; age-related disease; mTORC1; mTORC2; rapamycin

DOI:  https://doi.org/10.1080/14756366.2021.1955873
Aging Cell. 2021 Jul 30. e13412

Decreased antiviral immune response within the central nervous system of aged mice is associated with increased lethality of West Nile virus encephalitis.

Kristen E Funk, Artem D Arutyunov, Pritesh Desai, James P White, Allison L Soung, Sarah F Rosen, Michael S Diamond, Robyn S Klein.

  West Nile virus (WNV) is an emerging pathogen that causes disease syndromes ranging from a mild flu-like illness to encephalitis. While the incidence of WNV infection is fairly uniform across age groups, the risk of lethal encephalitis increases with advanced age. Prior studies have demonstrated age-related, functional immune deficits that limit systemic antiviral immunity and increase mortality; however, the effect of age on antiviral immune responses specifically within the central nervous system (CNS) is unknown. Here, we show that aged mice exhibit increased peripheral organ and CNS tissue viral burden, the latter of which is associated with alterations in activation of both myeloid and lymphoid cells compared with similarly infected younger animals. Aged mice exhibit lower MHCII expression by microglia, and higher levels of PD1 and lower levels of IFNγ expression by WNV-specific CD8+ T cells in the CNS and CD8+ CD45+ cells. These data indicate that the aged CNS exhibits limited local reactivation of T cells during viral encephalitis, which may lead to reduced virologic control at this site.

Keywords:  CNS; West Nile virus; aging; antiviral T cells; microglia; viral encephalitis

DOI:  https://doi.org/10.1111/acel.13412
Proc Natl Acad Sci U S A. 2021 Aug 03. pii: e2025539118. [Epub ahead of print]118(31):

The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs.

Ephrath Tesfaye, Elena Martinez-Terroba, Jordan Bendor, Lauren Winkler, Christiane Olivero, Kevin Chen, David M Feldser, Jesse R Zamudio, Nadya Dimitrova.

  The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest.

Keywords:  lncRNA; p53; senescence; transcription; tumor suppression

DOI:  https://doi.org/10.1073/pnas.2025539118
Cell Death Dis. 2021 Jul 26. 12(8): 738

HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity.

Wenwei Luo, Jingyan Li, Ziqing Li, Tong Lin, Lili Zhang, Wanqi Yang, Yanqi Mai, Ruiming Liu, Meiting Chen, Chunmei Dai, Hanwei Yang, Jing Lu, Hong Li, Guimei Guan, Min Huang, Peiqing Liu, Zhuoming Li.

Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.

DOI: https://doi.org/10.1038/s41419-021-04035-6
Front Immunol. 2021 ;12 685139

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis.

Carmen Picón, Amalia Tejeda-Velarde, José Ignacio Fernández-Velasco, Manuel Comabella, Roberto Álvarez-Lafuente, Ester Quintana, Susana Sainz de la Maza, Enric Monreal, Noelia Villarrubia, José Carlos Álvarez-Cermeño, María Inmaculada Domínguez-Mozo, Lluís Ramió-Torrentà, Eulalia Rodríguez-Martín, Ernesto Roldán, Yolanda Aladro, Silvia Medina, Mercedes Espiño, Jaime Masjuan, Clara Matute-Blanch, Marta Muñoz-San Martín, Carmen Espejo, Carmen Guaza, Alfonso Muriel, Lucienne Costa-Frossard, Luisa María Villar.

  Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.

Keywords:  adaptive immunity; aging; inflammation; innate immunity; multiple sclerosis

DOI:  https://doi.org/10.3389/fimmu.2021.685139
J Exp Clin Cancer Res. 2021 Jul 29. 40(1): 243

Cellular senescence or stemness: hypoxia flips the coin.

Daniel Otero-Albiol, Amancio Carnero.

  Cellular senescence is a complex physiological state whose main feature is proliferative arrest. Cellular senescence can be considered the reverse of cell immortalization and continuous tumor growth. However, cellular senescence has many physiological functions beyond being a putative tumor suppressive trait. It remains unknown whether low levels of oxygen or hypoxia, which is a feature of every tissue in the organism, modulate cellular senescence, altering its capacity to suppress the limitation of proliferation. It has been observed that the lifespan of mammalian primary cells is increased under low oxygen conditions. Additionally, hypoxia promotes self-renewal and pluripotency maintenance in adult and embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and cancer stem cells (CSCs). In this study, we discuss the role of hypoxia facilitating senescence bypass during malignant transformation and acquisition of stemness properties, which all contribute to tumor development and cancer disease aggressiveness.

Keywords:  cancer; cellular senescence; dedifferentiation; hypoxia; immortalization; oxygen; stemness

DOI:  https://doi.org/10.1186/s13046-021-02035-0
Oxid Med Cell Longev. 2021 ;2021 9969842

LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells.

Dong Hwan Ho, Daleum Nam, Mi Kyoung Seo, Sung Woo Park, Wongi Seol, Ilhong Son.

Background: Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated with the dysregulation of the proteolytic pathway and mitochondrial dysfunction, which are also associated with the aggregation of α-synuclein (α-syn).
Methods: Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h. The markers of cellular senescence, including p53, p21Waf1/Cip1 (p21), β-galactosidase (β-gal), Rb phosphorylation, senescence-associated (SA) β-gal activity, and lysosomal activity, were examined. The dSH cells and rat primary cortical neurons were treated with α-syn fibrils 30 min before treatment with rotenone in the presence or absence of GSK-KI for 48 h. Mice were intraperitoneally injected with rotenone and MLi-2 (LRRK2 kinase inhibitor) once every two days for two weeks.
Results: Rotenone upregulated LRRK2 phosphorylation and β-gal levels through the activation of the p53-p21 signaling axis and downregulated Rb phosphorylation. Additionally, rotenone upregulated SA β-gal activity, reactive oxygen species levels, and LRRK2 phosphorylation and inhibited lysosome activity. Rotenone-induced LRRK2 upregulation impaired the clearance of α-syn fibrils. Treatment with LRRK2 inhibitor mitigated rotenone-induced cellular senescence and α-syn accumulation.
Conclusions: Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced α-syn accumulation. However, the administration of an LRRK2 kinase inhibitor rejuvenated rotenone-induced cellular senescence.

DOI: https://doi.org/10.1155/2021/9969842
Aging (Albany NY). 2021 Jul 28. 13(undefined):

Features of age-related response to sleep deprivation: in vivo experimental studies.

Maria Novozhilova, Tatiana Mishchenko, Elena Kondakova, Tatiana Lavrova, Maria Gavrish, Svetlana Aferova, Claudio Franceschi, Maria Vedunova.

  Insomnia is currently considered one of the potential triggers of accelerated aging. The frequency of registered sleep-wake cycle complaints increases with age and correlates with the quality of life of elderly people. Nevertheless, whether insomnia is actually an age-associated process or whether it acts as an independent stress-factor that activates pathological processes, remains controversial. In this study, we analyzed the effects of long-term sleep deprivation modeling on the locomotor and orienting-exploratory activity, spatial learning abilities and working memory of C57BL/6 female mice of different ages. We also evaluated the modeled stress influence on morphological changes in brain tissue, the functional activity of the mitochondrial apparatus of nerve cells, and the level of DNA methylation and mRNA expression levels of the transcription factor HIF-1α (Hif1) and age-associated molecular marker PLIN2. Our findings point to the age-related adaptive capacity of female mice to the long-term sleep deprivation influence. For young (1.5 months) mice, the modeled sleep deprivation acts as a stress factor leading to weight loss against the background of increased food intake, the activation of animals' locomotor and exploratory activity, their mnestic functions, and molecular and cellular adaptive processes ensuring animal resistance both to stress and risk of accelerated aging development. Sleep deprivation in adult (7-9 months) mice is accompanied by an increase in body weight against the background of active food intake, increased locomotor and exploratory activity, gross disturbances in mnestic functions, and decreased adaptive capacity of brain cells, that potentially increasing the risk of pathological reactions and neurodegenerative processes.

Keywords:  DNA methylation; PLIN2; aging; learning ability; sleep deprivation

DOI:  https://doi.org/10.18632/aging.203372
Sci Rep. 2021 Jul 30. 11(1): 15569

Telomere associated gene expression as well as TERT protein level and telomerase activity are altered in the ovarian follicles of aged mice.

Esra Gozde Kosebent, Saffet Ozturk.

Telomeres cap the ends of eukaryotic chromosomes to maintain genomic stability and integrity during an organism's lifespan. The length of telomeres inevitably shortens due to DNA replication, genotoxic agents, and biological aging. A limited number of cell types, e.g., stem cells, germline cells, and early embryos can elongate shortened telomeres via the enzymatic action of telomerase, which is composed of telomerase reverse transcriptase (TERT) and telomerase RNA component (Terc). Additionally, telomere-associated proteins including telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), as well as protection of telomeres 1a (POT1a), bind to telomeres to maintain their structural integrity and length. During ovarian aging in mammals, telomeres progressively shorten, accompanied by fertility loss; however, the molecular mechanism underlying this attrition during follicle development remains unclear. In this study, the primary, secondary, preantral, and antral follicles were obtained either from 6-week-old adult (n = 19) or 52-week-old aged (n = 12) mice. We revealed that the Tert, Terc, Trf1, Trf2, and Pot1a gene expression (P < 0.001) and TERT protein (P < 0.01) levels significantly decreased in certain ovarian follicles of the aged group when compared to those of the adult group. Also, telomerase activity exhibited remarkable changes in the follicles of both groups. Consequently, altered telomere-associated gene expression and reduced TERT protein levels in the follicles of aged mice may be a determinant of telomere shortening during ovarian aging, and infertility appearing in the later decades of reproductive lifespan. Further investigations are required to determine the molecular mechanisms underlying these alterations in the follicles during ovarian aging.

DOI: https://doi.org/10.1038/s41598-021-95239-5
Dis Model Mech. 2021 Jul 27. pii: dmm.048995. [Epub ahead of print]

TFAM-deficient mouse skin fibroblasts: an ex vivo model of mitochondrial dysfunction.

Manuel J Del Rey, Carolina Meroño, Cristina Municio, Alicia Usategui, María Mittelbrunn, Inés García-Consuegra, Gabriel Criado, José L Pablos.

  Mitochondrial dysfunction in different cell types is associated to several pathological processes and potentially contributes to chronic inflammatory and ageing-related diseases. Mitochondrial Transcription Factor A (TFAM) plays a critical role in maintaining mtDNA integrity and function. Taking advantage of the Tfamfl/fl UBC-Cre/ERT2+/+ mice, we sought to develop a cellular in vitro system to investigate the role of mitochondrial dysfunction in the stromal cell component. We describe an inducible model of mitochondrial dysfunction by stable depletion of TFAM in primary mouse skin fibroblast (SK-FB) after 4-hydroxytamoxifen (4-OHT) administration. Tfam gene deletion caused a sustained reduction of Tfam and mtDNA-encoded mRNA expression in Cre(+) cultured for low (LP) and high passages (HP). Ultimately, Tfam knockout translated into a loss of TFAM protein. TFAM depletion led to a substantial reduction of the mitochondrial respiratory chain (MRC) complexes that was exacerbated in HP SK-FB cultures. The assembly pattern showed that the respiratory complexes fail to reach the respirasome in 4-OHT Cre(+) SK-FB. Functionally, we determined the mitochondrial function and the glycolytic activity by mito-stress and glycolysis-stress test respectively. These analysis showed that mitochondrial dysfunction was developed after long-term 4-OHT treatment in HP Cre(+) SK-FB and was compensated by an increase in the glycolytic capacity. Finally, expression analysis revealed that 4-OHT-treated HP Cre(+) SK-FB showed a senescent and pro-inflammatory phenotype. In conclusion, we have generated and validated the first ex vivo model of fibroblast mitochondrial dysfunction that results in a pro-inflammatory phenotype applicable to explore this process in other cell types in a variety of pathological conditions.

Keywords:  Cellular senescence; Fibroblasts; Inflammation; Mitochondrial dysfunction; TFAM

DOI:  https://doi.org/10.1242/dmm.048995
J Cell Physiol. 2021 Jul 28.

Nampt affects mitochondrial function in aged oocytes by mediating the downstream effector FoxO3a.

Qingrui Zhuan, Jun Li, Xingzhu Du, Luyao Zhang, Lin Meng, Keren Cheng, Shien Zhu, Yunpeng Hou, Xiangwei Fu.

  Maternal aging can impair the quality and decrease the developmental competence of ovulated oocytes. In this study, compromised germinal vesicle breakdown (GVBD) was found in aged mice oocytes. Furthermore, we observed increased reactive oxygen species (ROS) and mitochondrial Ca2+ levels, along with reduced mitochondrial temperature in aged oocytes. Maternal aging also changed the crotonylation level in oocytes. Forkhead box O3 (FoxO3a), a member of the forkhead protein family involved in the regulation of cell survival and life span reached a peak level in the metaphase II stage. Compared with a younger group, FoxO3a expression increased in aged oocytes. Intracellular localization of FoxO3a changed from the cytoplasm to chromatin in response to aging. The expression of the upstream regulator nicotinamide-phosphoribosyltransferase (Nampt) peaked in the GVBD stage. Moreover, Nampt expression was increased in aged oocytes, and more intense staining of Nampt was found in aged mice ovary. To further study the role of Nampt in mitochondrial function, specific agonist P7C3 and inhibitor FK866 were applied to aged oocytes, and FK866 significantly decreased adenosine triphosphate and mitochondrial membrane potential. In conclusion, mitochondrial dysfunction in aged oocytes was associated with elevated FoxO3a, and suppression of Nampt could further impair mitochondrial function.

Keywords:  FoxO3a; Nampt; maternal-aging; mitochondria; oocyte

DOI:  https://doi.org/10.1002/jcp.30532
Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00833-0. [Epub ahead of print]36(4): 109420

Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis.

Yuhao Liu, Ying Zhao, Yousef Shukha, Haocheng Lu, Lu Wang, Zhipeng Liu, Cai Liu, Yang Zhao, Huilun Wang, Guizhen Zhao, Wenying Liang, Yanbo Fan, Lin Chang, Arif Yurdagul, Christopher B Pattillo, A Wayne Orr, Michael Aviram, Bo Wen, Minerva T Garcia-Barrio, Jifeng Zhang, Wanqing Liu, Duxin Sun, Tony Hayek, Y Eugene Chen, Oren Rom.

  Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. In this study, we demonstrate impaired glycine-oxalate metabolism through alanine-glyoxylate aminotransferase (AGXT) in atherosclerosis. As found in patients with atherosclerosis, the glycine/oxalate ratio is decreased in atherosclerotic mice concomitant with suppression of AGXT. Agxt deletion in apolipoprotein E-deficient (Apoe-/-) mice decreases the glycine/oxalate ratio and increases atherosclerosis with induction of hepatic pro-atherogenic pathways, predominantly cytokine/chemokine signaling and dysregulated redox homeostasis. Consistently, circulating and aortic C-C motif chemokine ligand 5 (CCL5) and superoxide in lesional macrophages are increased. Similar findings are observed following dietary oxalate overload in Apoe-/- mice. In macrophages, oxalate induces mitochondrial dysfunction and superoxide accumulation, leading to increased CCL5. Conversely, AGXT overexpression in Apoe-/- mice increases the glycine/oxalate ratio and decreases aortic superoxide, CCL5, and atherosclerosis. Our findings uncover dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.

Keywords:  AGXT; CCL5; amino acids; atherosclerosis; glycine; mitochondrial dysfunction; oxalate

DOI:  https://doi.org/10.1016/j.celrep.2021.109420
Aging Cell. 2021 Jul 27. e13444

Nrf2 deficiency decreases NADPH from impaired IDH shuttle and pentose phosphate pathway in retinal pigmented epithelial cells to magnify oxidative stress-induced mitochondrial dysfunction.

Marisol Cano, Sayantan Datta, Lei Wang, Tongyun Liu, Miguel Flores-Bellver, Mira Sachdeva, Debasish Sinha, James T Handa.

  The nuclear factor-erythroid 2-related factor-2 (Nrf2), a major antioxidant transcription factor, is decreased in several age-related diseases including age-related macular degeneration (AMD), the most common cause of blindness among the elderly in western society. Since Nrf2's mito-protective response is understudied, we investigated its antioxidant response on mitochondria. Control and Nrf2-deficient retinal pigmented epithelial (RPE) cells were compared after treating with cigarette smoke extract (CSE). Mitochondrial antioxidant abundance and reactive oxygen species (ROS) were quantified. Mitochondrial function was assessed by TMRM assay, NADPH, electron transport chain activity, and Seahorse. Results were corroborated in Nrf2-/- mice and relevance to AMD was provided by immunohistochemistry of human globes. CSE induced mitochondrial ROS to impair mitochondrial function. H2 O2 increase in particular, was magnified by Nrf2 deficiency, and corresponded with exaggerated mitochondrial dysfunction. While Nrf2 did not affect mitochondrial antioxidant abundance, oxidized PRX3 was magnified by Nrf2 deficiency due to decreased NADPH from decreased expression of IDH2 and pentose phosphate pathway (PPP) genes. With severe CSE stress, intrinsic apoptosis was activated to increase cell death. PPP component TALDO1 immunolabeling was decreased in dysmorphic RPE of human AMD globes. Despite limited regulation of mitochondrial antioxidant expression, Nrf2 influences PPP and IDH shuttle activity that indirectly supplies NADPH for the TRX2 system. These results provide insight into how Nrf2 deficiency impacts the mitochondrial antioxidant response, and its role in AMD pathobiology.

Keywords:  aging; mitochondria; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1111/acel.13444
Mol Omics. 2021 Jul 30.

Transcriptome features of striated muscle aging and predictability of protein level changes.

Yu Han, Lauren Z Li, Nikhitha L Kastury, Cody T Thomas, Maggie P Y Lam, Edward Lau.

We performed total RNA sequencing and multi-omics analysis comparing skeletal muscle and cardiac muscle in young adult (4 months) vs. early aging (20 months) mice to examine the molecular mechanisms of striated muscle aging. We observed that aging cardiac and skeletal muscles both invoke transcriptomic changes in innate immune system and mitochondria pathways but diverge in extracellular matrix processes. On an individual gene level, we identified 611 age-associated signatures in skeletal and cardiac muscles, including a number of myokine and cardiokine encoding genes. Because RNA and protein levels correlate only partially, we reason that differentially expressed transcripts that accurately reflect their protein counterparts will be more valuable proxies for proteomic changes and by extension physiological states. We applied a computational data analysis workflow to estimate which transcriptomic changes are more likely relevant to protein-level regulation using large proteogenomics data sets. We estimate about 48% of the aging-associated transcripts predict protein levels well (r ≥ 0.5). In parallel, a comparison of the identified aging-regulated genes with public human transcriptomics data showed that only 35-45% of the identified genes show an age-dependent expression in corresponding human tissues. Thus, integrating both RNA-protein correlation and human conservation across data sources, we nominate 134 prioritized aging striated muscle signatures that are predicted to correlate strongly with protein levels and that show age-dependent expression in humans. The results here reveal new details into how aging reshapes gene expression in striated muscles at the transcript and protein levels.

DOI: https://doi.org/10.1039/d1mo00178g
Neurobiol Aging. 2021 Jun 20. pii: S0197-4580(21)00206-2. [Epub ahead of print]106 241-256

Age-related neuroinflammation and pathology in the locus coeruleus and hippocampus: beta-adrenergic antagonists exacerbate impairment of learning and memory in aged mice.

Andrew K Evans, Heui Hye Park, Nay Lui Saw, Kratika Singhal, Gaku Ogawa, Ryan D Leib, Mehrdad Shamloo.

  The locus coeruleus (LC) provides the primary noradrenergic input to the forebrain and hippocampus, and may be vulnerable to degeneration and contribute to age-related cognitive decline and neuroinflammation. Additionally, inhibition of noradrenergic transmission by brain-permeable beta-blockers could exacerbate cognitive impairment. This study examined effects of age and acute beta-blocker administration on LC and hippocampus pathology, neuroinflammation and learning and memory behavior in mice. Male mice, 3 and 18 months old, were administered propranolol (beta-blocker) or mabuterol (beta-adrenergic agonist) acutely around behavioral assessment. Terminal inflammatory markers in plasma, hippocampus and LC were assessed alongside histopathology. An increase in hippocampal and LC microgliosis and inflammatory proteins in the hippocampus was detected in aged mice. We report pathological hyperphosphorylation of the postsynaptic NMDA receptor subunit 2B (NR2B) in the hippocampus, suggesting neuronal hyperexcitability. Furthermore, the aged proteome revealed an induction in proteins related to energy metabolism, and mitochondria dysfunction in the LC and hippocampus. In a series of hippocampal dependent behavioral assessment tasks acute beta-adrenergic agonist or beta blocker administration altered learning and memory behavior in both aged and young mice. In Y-maze, propranolol and mabuterol differentially altered time spent in novel versus familiar arms in young and aged mice. Propranolol impaired Novel Object Recognition in both young and aged mice. Mabuterol enhanced trace learning in fear conditioning. Aged mice froze more to context and less to cue. Propranolol impaired contextual recall in aged mice. Concluding, aged mice show LC and hippocampus pathology and heightened effects of beta-adrenergic pharmacology on learning and memory.

Keywords:  Aging; Behavior; Beta-blocker; Inflammation; Locus coeruleus; proteomics

DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.06.012
Adv Drug Deliv Rev. 2021 Jul 24. pii: S0169-409X(21)00278-7. [Epub ahead of print] 113886

Anti-aging properties of phytoconstituents and phyto-nanoemulsions and their application in managing aging-related diseases.

Feng Xue, Xuan Li, Linxi Qin, Xinye Liu, Chen Li, Benu Adhikari.

  Aging is spontaneous and inevitable process in all living beings. It is a complex natural phenomenon that manifests as a gradual decline of physiological functions and homeostasis. Aging inevitably leads to age-associated injuries, diseases, and eventually death. The research on aging-associated diseases aimed at delaying, preventing or even reversing the aging process are of great significance for healthy aging and also for scientific progress. Numerous plant-derived compounds have anti-aging effects, but their therapeutic potential is limited due to their short shelf-life and low bioavailability. As the novel delivery system, nanoemulsion can effectively improve this defect. Nanoemulsions enhance the delivery of drugs to the target site, maintain the plasma concentration for a longer period, and minimize adverse reaction and side effects. This review describes the importance of nanoemulsions for the delivery of phyto-derived compounds and highlights the importance of nanoemulsions in the treatment of aging-related diseases. It also covers the methods of preparation, fate and safety of nanoemulsions, which will provide valuable information for the development of new strategies in treatment of aging-related diseases.

Keywords:  Aging; Diseases; Effectiveness; Mechanism; Nanoemulsion; Phytoconstituents

DOI:  https://doi.org/10.1016/j.addr.2021.113886
Nature. 2021 Jul 28.

Rewiring of the ubiquitinated proteome determines ageing in C. elegans.

Seda Koyuncu, Rute Loureiro, Hyun Ju Lee, Prerana Wagle, Marcus Krueger, David Vilchez.

Ageing is driven by a loss of cellular integrity1. Given the major role of ubiquitin modifications in cell function2, here we assess the link between ubiquitination and ageing by quantifying whole-proteome ubiquitin signatures in Caenorhabditis elegans. We find a remodelling of the ubiquitinated proteome during ageing, which is ameliorated by longevity paradigms such as dietary restriction and reduced insulin signalling. Notably, ageing causes a global loss of ubiquitination that is triggered by increased deubiquitinase activity. Because ubiquitination can tag proteins for recognition by the proteasome3, a fundamental question is whether deficits in targeted degradation influence longevity. By integrating data from worms with a defective proteasome, we identify proteasomal targets that accumulate with age owing to decreased ubiquitination and subsequent degradation. Lowering the levels of age-dysregulated proteasome targets prolongs longevity, whereas preventing their degradation shortens lifespan. Among the proteasomal targets, we find the IFB-2 intermediate filament4 and the EPS-8 modulator of RAC signalling5. While increased levels of IFB-2 promote the loss of intestinal integrity and bacterial colonization, upregulation of EPS-8 hyperactivates RAC in muscle and neurons, and leads to alterations in the actin cytoskeleton and protein kinase JNK. In summary, age-related changes in targeted degradation of structural and regulatory proteins across tissues determine longevity.

DOI: https://doi.org/10.1038/s41586-021-03781-z
Diabetes Obes Metab. 2021 Jul 28.

SGLT2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body-induced NRF2 activation.

Mi Na Kim, Joon Ho Moon, Young Min Cho.

   AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the progression of diabetic kidney disease. However, the mechanisms underlying this renoprotective benefit are not completely understood. We evaluated whether SGLT2 inhibition reduces cellular senescence in the kidney and investigated the molecular pathways involved in the renoprotective effect.
MATERIALS AND METHODS: Dapagliflozin (1 mg/kg), glimepiride (2.5 mg/kg), or vehicle was administered daily via oral gavage for 8 weeks in db/db mice. Expression levels of ageing marker genes (p21, p16, and p53) and oxidative stress were measured in the kidney using real-time RT-PCR, immunohistochemistry, and western blot analysis. For in vitro analysis, HK-2 cells, a human renal tubular epithelial cell line, were pretreated with H2 O2 to induce cellular senescence, and the levels of ageing markers were measured after treatment with β-hydroxybutyrate (β-HB) or NRF2-specific siRNA.
RESULTS: Expression levels of ageing marker genes (p21, p16, and p53) and senescence-associated secretory phenotypes of the kidney were increased in the vehicle-treated db/db (db/db+vehicle) group compared with the db/+ group, and this increase was markedly reversed in the dapagliflozin-treated db/db (db/db+SGLT2i) group, but not in the glimepiride-treated db/db (db/db+SU) group. In the kidneys of mice in the db/db+SGLT2i group, oxidative stress and DNA damage were also reduced compared with those in the db/db+vehicle and db/db+SU groups. Dapagliflozin increased plasma β-HB, which reduced H2 O2 -induced DNA damage and senescence in HK-2 cells. β-HB-induced NRF2 nuclear translocation mediated anti-senescent effects by inducing antioxidant pathways.
CONCLUSIONS: Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone-induced NRF2 activation. This article is protected by copyright. All rights reserved.

Keywords:  NRF2; SGLT2 inhibitor; diabetic kidney disease; ketone body; senescence

DOI:  https://doi.org/10.1111/dom.14503
Adv Geriatr Med Res. 2021 ;pii: e210015. [Epub ahead of print]3(3):

Naïve T Cell Quiescence in Immune Aging.

Claire E Gustafson.

  Naïve T cells are critical for protection against emerging viral and bacterial infections. However, the ability of these cells to elicit effective long-term immune responses declines with age and contributes to increased disease susceptibility in older individuals. This decline has been linked with the breakdown of cellular quiescence that causes partial differentiation of naïve T cells with age, but the underlying mediators of this breakdown are unclear. Comparisons to stem cell quiescence in mice and man offer insight into naïve T cells and aging. However, the utilization of single cell technologies in combination with advances in the biology of human tissue aging is needed to provide further understanding of naïve T cell complexity and quiescence breakdown with age.

Keywords:  cellular homeostasis; differentiation; immune aging; stem cells; tissue niches

DOI:  https://doi.org/10.20900/agmr20210015
Nat Commun. 2021 07 27. 12(1): 4543

The trans-omics landscape of COVID-19.

Peng Wu, Dongsheng Chen, Wencheng Ding, Ping Wu, Hongyan Hou, Yong Bai, Yuwen Zhou, Kezhen Li, Shunian Xiang, Panhong Liu, Jia Ju, Ensong Guo, Jia Liu, Bin Yang, Junpeng Fan, Liang He, Ziyong Sun, Ling Feng, Jian Wang, Tangchun Wu, Hao Wang, Jin Cheng, Hui Xing, Yifan Meng, Yongsheng Li, Yuanliang Zhang, Hongbo Luo, Gang Xie, Xianmei Lan, Ye Tao, Jiafeng Li, Hao Yuan, Kang Huang, Wan Sun, Xiaobo Qian, Zhichao Li, Mingxi Huang, Peiwen Ding, Haoyu Wang, Jiaying Qiu, Feiyue Wang, Shiyou Wang, Jiacheng Zhu, Xiangning Ding, Chaochao Chai, Langchao Liang, Xiaoling Wang, Lihua Luo, Yuzhe Sun, Ying Yang, Zhenkun Zhuang, Tao Li, Lei Tian, Shaoqiao Zhang, Linnan Zhu, Ashley Chang, Lei Chen, Yiquan Wu, Xiaoyan Ma, Fang Chen, Yan Ren, Xun Xu, Siqi Liu, Jian Wang, Huanming Yang, Lin Wang, Chaoyang Sun, Ding Ma, Xin Jin, Gang Chen.

The outbreak of coronavirus disease 2019 (COVID-19) is a global health emergency. Various omics results have been reported for COVID-19, but the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here we collect blood samples from 231 COVID-19 patients, prefiltered to exclude those with selected comorbidities, yet with symptoms ranging from asymptomatic to critically ill. Using integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles, we report a trans-omics landscape for COVID-19. Our analyses find neutrophils heterogeneity between asymptomatic and critically ill patients. Meanwhile, neutrophils over-activation, arginine depletion and tryptophan metabolites accumulation correlate with T cell dysfunction in critical patients. Our multi-omics data and characterization of peripheral blood from COVID-19 patients may thus help provide clues regarding pathophysiology of and potential therapeutic strategies for COVID-19.

DOI: https://doi.org/10.1038/s41467-021-24482-1
Front Cell Dev Biol. 2021 ;9 703466

A Tale of Two States: Pluripotency Regulation of Telomeres.

Clara Lopes Novo.

  Inside the nucleus, chromatin is functionally organized and maintained as a complex three-dimensional network of structures with different accessibility such as compartments, lamina associated domains, and membraneless bodies. Chromatin is epigenetically and transcriptionally regulated by an intricate and dynamic interplay of molecular processes to ensure genome stability. Phase separation, a process that involves the spontaneous organization of a solution into separate phases, has been proposed as a mechanism for the timely coordination of several cellular processes, including replication, transcription and DNA repair. Telomeres, the repetitive structures at the end of chromosomes, are epigenetically maintained in a repressed heterochromatic state that prevents their recognition as double-strand breaks (DSB), avoiding DNA damage repair and ensuring cell proliferation. In pluripotent embryonic stem cells, telomeres adopt a non-canonical, relaxed epigenetic state, which is characterized by a low density of histone methylation and expression of telomere non-coding transcripts (TERRA). Intriguingly, this telomere non-canonical conformation is usually associated with chromosome instability and aneuploidy in somatic cells, raising the question of how genome stability is maintained in a pluripotent background. In this review, we will explore how emerging technological and conceptual developments in 3D genome architecture can provide novel mechanistic perspectives for the pluripotent epigenetic paradox at telomeres. In particular, as RNA drives the formation of LLPS, we will consider how pluripotency-associated high levels of TERRA could drive and coordinate phase separation of several nuclear processes to ensure genome stability. These conceptual advances will provide a better understanding of telomere regulation and genome stability within the highly dynamic pluripotent background.

Keywords:  chromatin; epigenetics; nuclear architecture; phase separation; pluripotency; telomeres

DOI:  https://doi.org/10.3389/fcell.2021.703466
Aging Cell. 2021 Jul 27. e13445

Telomere length and metabolic syndrome traits: A Mendelian randomisation study.

Nellie Y Loh, Raymond Noordam, Constantinos Christodoulides.

  Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty-two independent variants identified at FDR<0.05 from a genome-wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary-level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two-sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR-Egger, weighted-median and MR-PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist-to-hip ratio adjusted for body mass index (β = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (β = 1.529 mmHg, SE = 0.332, p = 4x10-6 ) and diastolic (β = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057-1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper-body fat distribution and raised blood pressure.

Keywords:  GWAS; Mendelian randomisation; adipose tissue; ageing; metabolic syndrome; telomeres

DOI:  https://doi.org/10.1111/acel.13445
NPJ Vaccines. 2021 Jul 27. 6(1): 93

Vaccination as a preventative measure contributing to immune fitness.

Béatrice Laupèze, Giuseppe Del Giudice, Mark T Doherty, Robbert Van der Most.

The primary goal of vaccination is the prevention of pathogen-specific infection. The indirect consequences may include maintenance of homeostasis through prevention of infection-induced complications; trained immunity that re-programs innate cells to respond more efficiently to later, unrelated threats; slowing or reversing immune senescence by altering the epigenetic clock, and leveraging the pool of memory B and T cells to improve responses to new infections. Vaccines may exploit the plasticity of the immune system to drive longer-term immune responses that promote health at a broader level than just the prevention of single, specific infections. In this perspective, we discuss the concept of "immune fitness" and how to potentially build a resilient immune system that could contribute to better health. We argue that vaccines may contribute positively to immune fitness in ways that are only beginning to be understood, and that life-course vaccination is a fundamental tool for achieving healthy aging.

DOI: https://doi.org/10.1038/s41541-021-00354-z