bims-senagi 2022-01-02 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–01–02
twenty papers selected by
Maria Grazia Vizioli, Mayo Clinic

Senescence-induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics.
CCAAT/enhancer-binding protein (C/EBP) homologous protein promotes alveolar epithelial cell senescence via the nuclear factor-kappa B pathway in pulmonary fibrosis.
Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system.
Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence.
Oridonin inhibits SASP by blocking p38 and NF-κB pathways in senescent cells.
Emerging rejuvenation strategies-Reducing the biological age.
Glyoxal induces senescence in human keratinocytes through oxidative stress and activation of the AKT/FOXO3a/p27KIP1 pathway.
Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells.
Targeting the Molecular & Cellular Pillars of Human Aging with Exercise.
α-1 Adrenergic receptor antagonist doxazosin reverses hepatic stellate cells activation via induction of senescence.
H3K4 Methylation in Aging and Metabolism.
1,25-Dihydroxyvitamin D deficiency induces sarcopenia by inducing skeletal muscle cell senescence.
Small molecule STING inhibition improves myocardial infarction remodeling.
Neutrophils and neutrophil extracellular trap components: emerging biomarkers and therapeutic targets for age-related eye diseases.
Bidirectional Association Between Sleep and Brain Atrophy in Aging.
The NLRP3 inflammasome in age-related eye disease: Evidence-based connexin hemichannel therapeutics.
Parathyroid hormone signaling in mature osteoblasts/osteocytes protects mice from age-related bone loss.
Calcification in Werner syndrome associated with lymphatic vessels aging.
Early manifestation of aging-related vascular dysfunction in human penile vasculature-A potential explanation for the role of erectile dysfunction as a harbinger of systemic vascular disease.
Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians.

Aging Cell. 2021 Dec 27. e13525

Senescence-induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics.

Erica C Lorenzo, Blake L Torrance, Spencer R Keilich, Iman Al-Naggar, Andrew Harrison, Ming Xu, Jenna M Bartley, Laura Haynes.

  Aging and senescence impact CD4 T helper cell (Th) subset differentiation during influenza infection. In the lungs of infected aged mice, there were significantly greater percentages of Th cells expressing the transcription factor FoxP3, indicative of regulatory CD4 T cells (Treg), when compared to young. TGF-beta levels, which drive FoxP3 expression, were also higher in the bronchoalveolar lavage of aged mice and blocking TGF-beta reduced the percentage of FoxP3+ Th in aged lungs during influenza infection. Since TGF-beta can be the product of senescent cells, these were targeted by treatment with senolytic drugs. Treatment of aged mice with senolytics prior to influenza infection restored the differentiation of Th cells in those aged mice to a more youthful phenotype with fewer Th cells expressing FoxP3. In addition, treatment with senolytic drugs induced differentiation of aged Th toward a healing Type 2 phenotype, which promotes a return to homeostasis. These results suggest that senescent cells, via production of cytokines such as TGF-beta, have a significant impact on Th differentiation.

Keywords:  T cells; aging; influenza; senescence; senolytics

DOI:  https://doi.org/10.1111/acel.13525
Int J Biochem Cell Biol. 2021 Dec 23. pii: S1357-2725(21)00223-5. [Epub ahead of print] 106142

CCAAT/enhancer-binding protein (C/EBP) homologous protein promotes alveolar epithelial cell senescence via the nuclear factor-kappa B pathway in pulmonary fibrosis.

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

  Alveolar epithelial cell senescence is a core event in the development of pulmonary fibrosis. Endoplasmic reticulum stress accelerates cellular senescence significantly; however, whether this stress promotes alveolar epithelial cell senescence in pulmonary fibrosis and its mechanisms are unclear. As a common intersection of endoplasmic reticulum stress signaling pathways, CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activates the oxidative stress pathway, which in turn accelerates cellular senescence. Therefore, we speculated CHOP pathway activation would affect endoplasmic reticulum stress-induced alveolar epithelial cell senescence in pulmonary fibrosis. In this study, we observed that alveolar epithelial cell senescence was accompanied by CHOP overexpression in idiopathic pulmonary fibrosis lung tissues. Bleomycin and tunicamycin combination models in vivo and in vitro showed that CHOP downregulation rescued alveolar epithelial cell senescence, reduced fibroblast activation mediated by the senescence-associated secretory phenotype, and improved pulmonary fibrosis pathology. Mechanistic studies showed that CHOP accelerated alveolar epithelial cell senescence by promoting reactive oxygen species generation, which activated the nuclear factor-kappa B pathway. Our study suggested that CHOP activates the downstream nuclear factor-kappa B pathway, thus contributing to endoplasmic reticulum stress-induced alveolar epithelial cell senescence and pulmonary fibrosis. DATA AVAILABILITY STATEMENT: All data generated or analyzed during this study are included in this published article.

Keywords:  Alveolar epithelial cell senescence; CCAAT/enhancer-binding protein (C/EBP) homologous protein; Endoplasmic reticulum stress; Pulmonary fibrosis; nuclear factor-kappa B

DOI:  https://doi.org/10.1016/j.biocel.2021.106142
Aging (Albany NY). 2021 Dec 26. 13(undefined):

Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system.

Charlotte Liisborg, Vibe Skov, Lasse Kjær, Hans Carl Hasselbalch, Torben Lykke Sørensen.

  The cause of age-related macular degeneration (AMD) is unknown, but evidence indicates that both innate and adaptive immunity play a role in the pathogenesis. Our recent work has investigated AMD in patients with myeloproliferative neoplasms (MPNs) since they have increased drusen and AMD prevalence. We have previously found increased levels of chronic low-grade inflammation (CLI) in MPN patients with drusen (MPNd) compared to MPN patients with normal retinas (MPNn). CLI and AMD are both associated with aging, and we, therefore, wanted to study immunosenescence markers in MPNd, MPNn, and AMD. The purpose was to identify differences between MPNd and MPNn, which might reveal novel information relevant to drusen pathophysiology and thereby the AMD pathogenesis. Our results suggest that MPNd have a T cell differentiation profile resembling AMD and more effector memory T cells than MPNn. The senescence-associated-secretory-phenotype (SASP) is associated with effector T cells. SASP is thought to play a role in driving CLI seen with advancing age. Senescent cells with SASP may damage healthy tissue, including the eye tissues affected in AMD. The finding of increased effector cells in MPNd could implicate a role for adaptive immunity and senescent T cells together with increased CLI in drusen pathophysiology.

Keywords:  T cells; age-related macular degeneration; chronic low-grade inflammation; drusen; immunosenescence; myeloproliferative neoplasms

DOI:  https://doi.org/10.18632/aging.203803
Nutrients. 2021 Dec 18. pii: 4550. [Epub ahead of print]13(12):

Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence.

Jacqueline Lena Boyajian, Merry Ghebretatios, Sabrina Schaly, Paromita Islam, Satya Prakash.

  The role of the microbiome in human aging is important: the microbiome directly impacts aging through the gastrointestinal system. However, the microbial impact on skin has yet to be fully understood. For example, cellular senescence is an intrinsic aging process that has been recently associated with microbial imbalance. With age, cells become senescent in response to stress wherein they undergo irreversible growth arrest while maintaining high metabolic activity. An accumulation of senescent cells has been linked to various aging and chronic pathologies due to an overexpression of the senescence-associated secretory phenotype (SASP) comprised of proinflammatory cytokines, chemokines, growth factors, proteases, lipids and extracellular matrix components. In particular, dermatological disorders may be promoted by senescence as the skin is a common site of accumulation. The gut microbiota influences cellular senescence and skin disruption through the gut-skin axis and secretion of microbial metabolites. Metabolomics can be used to identify and quantify metabolites involved in senescence. Moreover, novel anti-senescent therapeutics are warranted given the poor safety profiles of current pharmaceutical drugs. Probiotics and prebiotics may be effective alternatives, considering the relationship between the microbiome and healthy aging. However, further research on gut composition under a senescent status is needed to develop immunomodulatory therapies.

Keywords:  cellular senescence; disease; dysbiosis; gut microbiome; microbial metabolites; nutrition; prebiotics; probiotics; skin

DOI:  https://doi.org/10.3390/nu13124550
Biochem Biophys Res Commun. 2021 Dec 28. pii: S0006-291X(21)01749-6. [Epub ahead of print]590 55-62

Oridonin inhibits SASP by blocking p38 and NF-κB pathways in senescent cells.

Shusuke Yasuda, Mano Horinaka, Yosuke Iizumi, Wakana Goi, Mamiko Sukeno, Toshiyuki Sakai.

  Cellular senescence is a state of irreversible cell growth arrest that functions as a biological defense mechanism against severe DNA damage. Senescent cells with DNA damage produce pro-inflammatory cytokines, such as IL-6 and IL-8, and this phenomenon is called the senescence-associated secretory phenotype (SASP). SASP factors have been implicated in various disorders, including cancer. We performed a screening assay and identified oridonin as a candidate SASP inhibitor. Oridonin is an active diterpenoid that is isolated from Isodon plants and has been reported to exhibit anti-inflammatory, antibacterial, antioxidant, and antitumor activities. It reduced the secretion of IL-6 and IL-8 in senescent cells at the protein and mRNA levels. Oridonin also inhibited p65 subunit of NF-κB activity. However, oridonin did not affect SA β-gal activity and enhanced the expression of p21. The expression and phosphorylation of p38 were down-regulated by oridonin. The p38 inhibitor SB203580 inhibited the secretion of IL-8, slightly inhibited the secretion of IL-6, and did not affect NF-κB activity. Therefore, the NF-κB and p38 pathways may contribute to the inhibition of SASP by oridonin. Oridonin has potential as a therapeutic agent for SASP-related diseases.

Keywords:  NF-κB; Oridonin; SASP; p38

DOI:  https://doi.org/10.1016/j.bbrc.2021.12.098
Aging Cell. 2021 Dec 31. e13538

Emerging rejuvenation strategies-Reducing the biological age.

Bohan Zhang, Alexandre Trapp, Csaba Kerepesi, Vadim N Gladyshev.

  Several interventions have recently emerged that were proposed to reverse rather than just attenuate aging, but the criteria for what it takes to achieve rejuvenation remain controversial. Distinguishing potential rejuvenation therapies from other longevity interventions, such as those that slow down aging, is challenging, and these anti-aging strategies are often referred to interchangeably. We suggest that the prerequisite for a rejuvenation intervention is a robust, sustained, and systemic reduction in biological age, which can be assessed by biomarkers of aging, such as epigenetic clocks. We discuss known and putative rejuvenation interventions and comparatively analyze them to explore underlying mechanisms.

Keywords:  aging; biomarkers; epigenetic clocks; rejuvenation

DOI:  https://doi.org/10.1111/acel.13538
J Invest Dermatol. 2021 Dec 28. pii: S0022-202X(21)02640-3. [Epub ahead of print]

Glyoxal induces senescence in human keratinocytes through oxidative stress and activation of the AKT/FOXO3a/p27KIP1 pathway.

Rym Halkoum, Virginie Salnot, Christophe Capallere, Christelle Plaza, Aurore L'Honoré, Karl Pays, Bertrand Friguet, Carine Nizard, Isabelle Petropoulos.

Senescence is a well-characterized cellular state associated with specific markers such as permanent cell proliferation arrest, and the secretion of messenger molecules by cells expressing the Senescence-Associated Secretory Phenotype (SASP). The SASP composition depends on many factors such as the cell type or the nature of the stress that induces senescence. Since the skin constitutes a barrier with the external environment, it is particularly subjected to different types of stresses, and consequently prone to premature cellular aging. The dicarbonyl compounds glyoxal and methylglyoxal are precursors of Advanced Glycation End-products (AGEs), whose presence marks normal and pathological aging. In this study, we demonstrate that glyoxal treatment provokes oxidative stress by increasing reactive oxygen species and AGEs levels and induces senescence in human keratinocytes. Furthermore, glyoxal-induced senescence bears a unique molecular progression profile: an "early-stage" when AKT-FOXO3a-p27KIP1 pathway mediates cell-cycle arrest, and a "late-stage" senescence maintained by the p16INK4/pRb pathway. Moreover, we characterized the resulting secretory phenotype during early senescence by mass spectrometry. Our study provides evidence that glyoxal can affect keratinocyte functions and act as a driver of human skin aging. Hence, senotherapeutics aimed at modulating glyoxal-associated senescence phenotype hold promising potential.

DOI: https://doi.org/10.1016/j.jid.2021.12.022
Front Cell Dev Biol. 2021 ;9 782841

Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells.

Irfan Khan, Marcel O Schmidt, Bhaskar Kallakury, Sidharth Jain, Shaunt Mehdikhani, Moshe Levi, Margarida Mendonca, William Welch, Anna T Riegel, Christopher S Wilcox, Anton Wellstein.

  Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16Ink4a-Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16Ink4a -dependent senescent cells by administration of AP20187. Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen and brain tissues. In the kidneys increased expression of ATM, p15 and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys. AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects.

Keywords:  INK-ATTAC; angiotensin II; endothelial cells; senescence; von Willebrand factor

DOI:  https://doi.org/10.3389/fcell.2021.782841
FEBS J. 2021 Dec 30.

Targeting the Molecular & Cellular Pillars of Human Aging with Exercise.

Jorming Goh, Esther Wong, Janjira Soh, Andrea Maier, Brian Kennedy.

  Biological aging is the main driver of age-associated chronic diseases. In 2014, the United States National Institute of Aging (NIA) sponsored a meeting between several investigators in the field of aging biology, who identified 7 biological pillars of aging and a consensus review, "Geroscience: Linking Aging to Chronic Disease," was published. The pillars of aging demonstrated the conservation of aging pathways in diverse model organisms and thus, represent a useful framework with which to study human aging. In this present review, we revisit the 7 pillars of aging from the perspective of exercise and discuss how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.

Keywords:  aging; disruption in proteostasis; dysregulated stress response; epigenetic drift; inflammaging; macromolecular damage; metabolic dysregulation; stem cell exhaustion

DOI:  https://doi.org/10.1111/febs.16337
Mech Ageing Dev. 2021 Dec 24. pii: S0047-6374(21)00190-1. [Epub ahead of print] 111617

α-1 Adrenergic receptor antagonist doxazosin reverses hepatic stellate cells activation via induction of senescence.

Sandra A Serna-Salas, Johanna C Arroyave-Ospina, Mengfan Zhang, Turtushikh Damba, Manon Buist-Homan, Martin H Muñoz-Ortega, Javier Ventura-Juárez, Han Moshage.

   BACKGROUND: Activated hepatic stellate cells (aHSCs) are the main effector cells during liver fibrogenesis. α-1 adrenergic antagonist doxazosin (DX) was shown to be anti-fibrotic in an in vivo model of liver fibrosis (LF), but the mechanism remains to be elucidated. Recent studies suggest that reversion of LF can be achieved by inducing cellular senescence characterized by irreversible cell-cycle arrest and acquisition of the senescence-associated secretory phenotype (SASP).
AIM: To elucidate the mechanism of the anti-fibrotic effect of DX and determine whether it induces senescence.
METHODS: Primary culture-activated rat HSCs were used. mRNA and protein expression were measured by qPCR and Western blot, respectively. Cell proliferation was assessed by BrdU incorporation and xCelligence analysis. TGF-β was used for maximal HSC activation. Norepinephrine (NE), PMA and m-3M3FBS were used to activate alpha-1 adrenergic signaling.
RESULTS: Expression of Col1α1 was significantly decreased by DX (10 µmol/L) at mRNA (-30 %) and protein level (-50 %) in TGF-β treated aHSCs. DX significantly reduced aHSCs proliferation and increased expression of senescence and SASP markers. PMA and m-3M3FBS reversed the effect of DX on senescence markers.
CONCLUSION: Doxazosin reverses the fibrogenic phenotype of aHSCs and induces the senescence phenotype.

Keywords:  Cell proliferation; Liver fibrosis; Norepinephrine; Phospholipase C; Protein kinase C; Senescence; Stellate cells; α1-Adrenergic signaling

DOI:  https://doi.org/10.1016/j.mad.2021.111617
Epigenomes. 2021 Jun 18. pii: 14. [Epub ahead of print]5(2):

H3K4 Methylation in Aging and Metabolism.

Chia-Ling Hsu, Yi-Chen Lo, Cheng-Fu Kao.

  During the process of aging, extensive epigenetic alterations are made in response to both exogenous and endogenous stimuli. Here, we summarize the current state of knowledge regarding one such alteration, H3K4 methylation (H3K4me), as it relates to aging in different species. We especially highlight emerging evidence that links this modification with metabolic pathways, which may provide a mechanistic link to explain its role in aging. H3K4me is a widely recognized marker of active transcription, and it appears to play an evolutionarily conserved role in determining organism longevity, though its influence is context specific and requires further clarification. Interestingly, the modulation of H3K4me dynamics may occur as a result of nutritional status, such as methionine restriction. Methionine status appears to influence H3K4me via changes in the level of S-adenosyl methionine (SAM, the universal methyl donor) or the regulation of H3K4-modifying enzyme activities. Since methionine restriction is widely known to extend lifespan, the mechanistic link between methionine metabolic flux, the sensing of methionine concentrations and H3K4me status may provide a cogent explanation for several seemingly disparate observations in aging organisms, including age-dependent H3K4me dynamics, gene expression changes, and physiological aberrations. These connections are not yet entirely understood, especially at a molecular level, and will require further elucidation. To conclude, we discuss some potential H3K4me-mediated molecular mechanisms that may link metabolic status to the aging process.

Keywords:  H3K4 methylation; aging; metabolism

DOI:  https://doi.org/10.3390/epigenomes5020014
Am J Transl Res. 2021 ;13(11): 12638-12649

1,25-Dihydroxyvitamin D deficiency induces sarcopenia by inducing skeletal muscle cell senescence.

Shuxiang Yu, Biqi Ren, Haiyun Chen, David Goltzman, Jianshe Yan, Dengshun Miao.

To determine if 1,25(OH)2D deficiency can induce age-related sarcopenia, the skeletal muscular phenotype of male wild-type (WT) and Cyp27b1 knockout (KO) mice were compared at 3 and 6 months of age. We found that muscle mass, grip strength and muscle fiber size were significantly decreased in aging Cyp27b1 KO male mice. The expression levels of genes related to mitochondrial metabolic activity, and antioxidant enzymes including SOD1, catalase, Nqo1 and Gcs were significantly down-regulated in skeletal muscle tissue of Cyp27b1 KO male mice; in contrast, the percentage of p16+ and p21+ myofibers, and the expression of p16, p19, p21, p53, TNFα, IL6 and MMP3 at mRNA and/or protein levels were significantly increased. We then injected tibialis anterior muscle of WT and Cyp27b1+/- male mice with BaCl2, and analyzed the regenerative ability of skeletal muscle cells 7 days later. The results revealed that the numbers of newly formed regenerating central nucleated fibers (CNF), the percentage of BrdU+ cells and the expression of MyoD, MyHC and Myf5 at mRNA levels were significantly down-regulated in the injured skeletal muscle tissue of Cyp27b1+/- mice. In summary, our studies indicate that 1,25(OH)2D deficiency can result in the development of age-related sarcopenia by inducing oxidative stress, skeletal muscular cell senescence and SASP, and by inhibiting skeletal muscle regeneration. Cyp27b1 KO mice can therefore be used as an animal model of age-related sarcopenia in order to investigate the pathogenesis of age-related sarcopenia and potentially to test intervention measures for treatment of sarcopenia.

Keywords: Vitamin D deficiency; muscular cell senescence and regeneration; oxidative stress; sarcopenia
Life Sci. 2021 Dec 28. pii: S0024-3205(21)01250-9. [Epub ahead of print] 120263

Small molecule STING inhibition improves myocardial infarction remodeling.

Lavinia Rech, Mahmoud Abdellatif, Maria Pöttler, Verena Stangl, Nishani Mabotuwana, Sean Hardy, Peter P Rainer.

   AIMS: Myocardial infarction (MI) is a major global cause of death. Massive cell death leads to inflammation, which is necessary for ensuing wound healing. Extensive inflammation, however, promotes infarct expansion and adverse remodeling. The DNA sensing receptor cyclic GMP-AMP synthase and its downstream signaling effector stimulator of interferon genes (cGAS-STING) is central in innate immune reactions in infections or autoimmunity. Cytosolic double-strand DNA activates the pathway and down-stream inflammatory responses. Recent papers demonstrated that this pathway is also active following MI and that its genetic targeting improves outcome. Thus, we investigated if pharmacologic pathway inhibition is protective after MI in order to test its translational potential.
MAIN METHODS: We investigated novel and selective small-molecule STING inhibitors that inhibit STING palmitoylation and multimerization and thereby downstream pathway activation in a preclinical murine MI model. We assessed structural and functional cardiac remodeling, infarct expansion and fibrosis, as well as cardiomyocyte hypertrophy and the expression of inflammatory genes.
KEY FINDINGS: Pharmacologic STING inhibition did not reduce mortality due to myocardial rupture in non-reperfused MI. Infarct size at day one was comparable. However, three weeks of pharmacologic STING inhibition after reperfused MI decreased infarct expansion and scarring, increased left ventricular systolic function to levels approaching normal values, and reduced myocardial hypertrophy.
SIGNIFICANCE: Selective small-molecule STING inhibition after myocardial infarction has the potential to improve wound healing responses and pathological remodeling and thereby attenuate the development of ischemic heart failure.

Keywords:  Fibrosis; Hypertrophy; Inflammation; Myocardial infarction; Remodeling; STING; cGAS

DOI:  https://doi.org/10.1016/j.lfs.2021.120263
Ageing Res Rev. 2021 Dec 28. pii: S1568-1637(21)00300-7. [Epub ahead of print] 101553

Neutrophils and neutrophil extracellular trap components: emerging biomarkers and therapeutic targets for age-related eye diseases.

Irene Martínez-Alberquilla, Xavier Gasull, Patricia Pérez-Luna, Rubén Seco-Mera, Javier Ruiz-Alcocer, Almudena Crooke.

  Age-related eye diseases, including dry eye, glaucoma, age-related macular degeneration, and diabetic retinopathy, represent a major global health issue based on their increasing prevalence and disabling action. Unraveling the molecular mechanisms underlying these diseases will provide novel opportunities to reduce the burden of age-related eye diseases and improve eye health, contributing to sustainable development goals achievement. The impairment of neutrophil extracellular traps formation/degradation processes seems to be one of these mechanisms. These traps formed by a meshwork of DNA and neutrophil cytosolic granule proteins may exacerbate the inflammatory response promoting chronic inflammation, a pivotal cause of age-related diseases. In this review, we describe current findings that suggest the role of neutrophils and their traps in the pathogenesis of the above-mentioned age-related eye diseases. Furthermore, we discuss why these cells and their constituents could be biomarkers and therapeutic targets for dry eye, glaucoma, age-related macular degeneration, and diabetic retinopathy. We also examine the therapeutic potential of some neutrophil function modulators and provide several recommendations for future research in age-related eye diseases.

Keywords:  Age-related macular degeneration; Diabetic retinopathy; Dry eye; Glaucoma; Neutrophil; Neutrophil extracellular trap

DOI:  https://doi.org/10.1016/j.arr.2021.101553
Front Aging Neurosci. 2021 ;13 726662

Bidirectional Association Between Sleep and Brain Atrophy in Aging.

Viktória Kokošová, Pavel Filip, David Kec, Marek Baláž.

  Human brain aging is characterized by the gradual deterioration of its function and structure, affected by the interplay of a multitude of causal factors. The sleep, a periodically repeating state of reversible unconsciousness characterized by distinct electrical brain activity, is crucial for maintaining brain homeostasis. Indeed, insufficient sleep was associated with accelerated brain atrophy and impaired brain functional connectivity. Concurrently, alteration of sleep-related transient electrical events in senescence was correlated with structural and functional deterioration of brain regions responsible for their generation, implying the interconnectedness of sleep and brain structure. This review discusses currently available data on the link between human brain aging and sleep derived from various neuroimaging and neurophysiological methods. We advocate the notion of a mutual relationship between the sleep structure and age-related alterations of functional and structural brain integrity, pointing out the position of high-quality sleep as a potent preventive factor of early brain aging and neurodegeneration. However, further studies are needed to reveal the causality of the relationship between sleep and brain aging.

Keywords:  brain aging; functional brain integrity; neuroimaging; sleep; structural brain integrity

DOI:  https://doi.org/10.3389/fnagi.2021.726662
Exp Eye Res. 2021 Dec 25. pii: S0014-4835(21)00477-2. [Epub ahead of print]215 108911

The NLRP3 inflammasome in age-related eye disease: Evidence-based connexin hemichannel therapeutics.

Odunayo O Mugisho, Colin R Green.

  The inflammasome pathway is a fundamental component of the innate immune system, playing a key role especially in chronic age-related eye diseases (AREDs). The inflammasome is of particular interest because it is a common disease pathway that once instigated, can amplify and perpetuate itself leading to chronic inflammation. With aging, it becomes more difficult to shut down inflammation after an insult but the common pathway means that a shared solution may be feasible that could be effective across multiple disease indications. This review focusses on the NLRP3 inflammasome, the most studied and characterized inflammasome in the eye. It describes the two-step signalling required for NLRP3 inflammasome complex activation, and provides evidence for its role in AREDs. In the final section, the article gives an overview of potential NLRP3 inflammasome targeting therapies, before presenting evidence for connexin hemichannel regulators as upstream blockers of inflammasome activation. These have shown therapeutic efficacy in multiple ocular disease models.

Keywords:  Age-related eye diseases; Connexin43; Hemichannels; Inflammasomes; NLRP3

DOI:  https://doi.org/10.1016/j.exer.2021.108911
Aging (Albany NY). 2021 Dec 30. 13(undefined):

Parathyroid hormone signaling in mature osteoblasts/osteocytes protects mice from age-related bone loss.

Yuhei Uda, Vaibhav Saini, Christopher A Petty, Majed Alshehri, Chao Shi, Jordan M Spatz, Roberto Santos, Carly M Newell, Tim Y Huang, Alejandro Kochen, Ji W Kim, Christodoulos K Constantinou, Hiroaki Saito, Kathryn D Held, Eric Hesse, Paola Divieti Pajevic.

  Aging is accompanied by osteopenia, characterized by reduced bone formation and increased bone resorption. Osteocytes, the terminally differentiated osteoblasts, are regulators of bone homeostasis, and parathyroid hormone (PTH) receptor (PPR) signaling in mature osteoblasts/osteocytes is essential for PTH-driven anabolic and catabolic skeletal responses. However, the role of PPR signaling in those cells during aging has not been investigated. The aim of this study was to analyze the role of PTH signaling in mature osteoblasts/osteocytes during aging. Mice lacking PPR in osteocyte (Dmp1-PPRKO) display an age-dependent osteopenia characterized by a significant decrease in osteoblast activity and increase in osteoclast number and activity. At the molecular level, the absence of PPR signaling in mature osteoblasts/osteocytes is associated with an increase in serum sclerostin and a significant increase in osteocytes expressing 4-hydroxy-2-nonenals, a marker of oxidative stress. In Dmp1-PPRKO mice there was an age-dependent increase in p16Ink4a/Cdkn2a expression, whereas it was unchanged in controls. In vitro studies demonstrated that PTH protects osteocytes from oxidative stress-induced cell death. In summary, we reported that PPR signaling in osteocytes is important for protecting the skeleton from age-induced bone loss by restraining osteoclast's activity and protecting osteocytes from oxidative stresses.

Keywords:  aging; osteocyte; osteoporosis; oxidative stress; parathyroid hormone

DOI:  https://doi.org/10.18632/aging.203808
Aging (Albany NY). 2021 Dec 27. 13(undefined):

Calcification in Werner syndrome associated with lymphatic vessels aging.

Hideyuki Ogata, Shinsuke Akita, Sanae Ikehara, Kazuhiko Azuma, Takashi Yamaguchi, Maihulan Maimaiti, Yoshiro Maezawa, Yoshitaka Kubota, Koutaro Yokote, Nobuyuki Mitsukawa, Yuzuru Ikehara.

  In addition to the symptoms of aging, the main symptoms in Werner syndrome (WS), a hereditary premature aging disease, include calcification of subcutaneous tissue with solid pain and refractory skin ulcers. However, the mechanism of calcification in WS remains unclear. In this study, the histological analysis of the skin around the ulcer with calcification revealed an accumulation of calcium phosphate in the lymphatic vessels. Moreover, the morphological comparison with the lymphatic vessels in PAD patients with chronic skin ulcers demonstrated the ongoing lymphatic remodeling in WS patients because of the narrow luminal cross-sectional area (LA) of the lymphatic vessels but the increment of lymphatic microvessels density (MLVD). Additionally, fluorescence immunohistochemical analysis presented the cytoplasmic distribution and the accumulation of WRN proteins in endothelial cells on remodeling lymphatic vessels. In summary, these results point out a relationship between calcification in lymphatic vessels and the remodeling of lymphatic vessels and suggest the significance of the accumulation of WRN mutant proteins as an age-related change in WS patients. Thus, cytoplasmic accumulation of WRN protein can be an indicator of the decreasing drainage function of the lymphatic vessels and the increased risk of skin ulcers and calcification in the lymphatic vessels.

Keywords:  Werner syndrome; calcification; endoplasmic reticulum stress; lymphatic vessel; skin ulcer

DOI:  https://doi.org/10.18632/aging.203789
Geroscience. 2021 Dec 28.

Early manifestation of aging-related vascular dysfunction in human penile vasculature-A potential explanation for the role of erectile dysfunction as a harbinger of systemic vascular disease.

Mariam El Assar, Javier Angulo, Esther García-Rojo, Alejandro Sevilleja-Ortiz, Borja García-Gómez, Argentina Fernández, Alberto Sánchez-Ferrer, José M La Fuente, Javier Romero-Otero, Leocadio Rodríguez-Mañas.

  Advanced age is related to functional alterations of human vasculature, but erectile dysfunction precedes systemic manifestations of vascular disease. The current study aimed to simultaneously evaluate the influence of aging on vascular function (relaxation and contraction responses) in systemic human vascular territories: aorta (HA) and resistance mesenteric arteries (HMA) and human corpus cavernosum (HCC) and penile resistance arteries (HPRA). Associations of oxidative stress and inflammation circulating biomarkers with age and functional responses were also determined. Vascular specimens were obtained from 76 organ donors (age range 18-87). Four age-groups were established: < 40, 40-55, 56-65 and > 65 years old. Increasing age was associated with a decline in endothelium-dependent relaxation induced by BK in HMA (r = -0.597, p = 0.0001), or by ACh in HCC (r = -0.505, p = 0.0022), and HPRA (r = -0.601, p = 0.0012). Significant impairment was detected at > 65 years old in HMA but earlier in penile vasculature (> 55 years old). Age-related reduction to H2O2-vasodilatory response started before in HCC (56-65 years old) than in HA (> 65 years old). In contrast to relaxation responses, aging-related hypercontractility to adrenergic stimulation was homogeneous: contractions significantly increased in subjects > 55 years old in all tested vessels. Although not significantly age related, circulating levels of ADMA (r = -0.681, p = 0.0052) and TNF-α (r = -0.537, p = 0.0385) were negatively correlated with endothelial vasodilation in HMA but not in HCC or HPRA. Penile vasculature exhibits an early impairment of endothelium-dependent and H2O2-induced vasodilations when compared to mesenteric microcirculation and aorta. Therefore, functional susceptibility of penile vasculature to the aging process may account for anticipation of erectile dysfunction to systemic manifestations of vascular disease.

Keywords:  Aorta; Biomarkers; Corpus cavernosum; Endothelial vasodilation; Erectile dysfunction; Human; Microvasculature; Vascular aging

DOI:  https://doi.org/10.1007/s11357-021-00507-x
Geroscience. 2021 Dec 29.

Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians.

Ines Sanchez-Roman, Beatriz Ferrando, Camilla Myrup Holst, Jonas Mengel-From, Signe Høi Rasmussen, Mikael Thinggaard, Vilhelm A Bohr, Kaare Christensen, Tinna Stevnsner.

  Oxidative stress is an important factor in age-associated neurodegeneration. Accordingly, mitochondrial dysfunction and genomic instability have been considered as key hallmarks of aging and have important roles in age-associated cognitive decline and neurodegenerative disorders. In order to evaluate whether maintenance of cognitive abilities at very old age is associated with key hallmarks of aging, we measured mitochondrial bioenergetics, mitochondrial DNA copy number and DNA repair capacity in peripheral blood mononuclear cells from centenarians in a Danish 1915 birth cohort (n = 120). Also, the circulating levels of brain-derived neurotrophic factor, NAD+ /NADH and carbonylated proteins were measured in plasma of the centenarians and correlated to cognitive capacity. Mitochondrial respiration was well preserved in the centenarian cohort when compared to young individuals (21-35 years of age, n = 33). When correlating cognitive performance of the centenarians with mitochondrial function such as basal respiration, ATP production, reserve capacity and maximal respiration, no overall correlations were observed, but when stratifying by sex, inverse associations were observed in the males (p < 0.05). Centenarians with the most severe cognitive impairment displayed the lowest activity of the central DNA repair enzyme, APE1 (p < 0.05). A positive correlation between cognitive capacity and levels of NAD+ /NADH was observed (p < 0.05), which may be because NAD+ /NADH consuming enzyme activities strive to reduce the oxidative DNA damage load. Also, circulating protein carbonylation was lowest in centenarians with highest cognitive capacity (p < 0.05). An opposite trend was observed for levels of brain-derived neurotrophic factor (p = 0.17). Our results suggest that maintenance of cognitive capacity at very old age may be associated with cellular mechanisms related to oxidative stress and DNA metabolism.

Keywords:  Centenarians; Cognition; DNA maintenance; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1007/s11357-021-00502-2