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Cytosolic nucleic acids as new markers of senescence and hyperglycemia-induced inflammation
Get PDFAging is characterized by a gradual functional decline resulting from a complex interaction between genetic, epigenetic and stochastic factors and the rate of aging is recognized as the most important risk factor for the development of the most common age-related diseases (ARDs). Research on aging process is currently focused on understanding the molecular mechanisms underlying age-related features accompanying on one hand, the onset of ARDs and on the other hand, the chances to reach a successful aging. A chronic, systemic, low-grade, age-related pro-inflammatory status, called “Inflammaging” is correlated with ARDs development. The two main culprits of inflammaging are the repeated stimulation of immune system over time and the increased burden of senescent cells. Senescent cells are able to modify the microenvironment acquiring a senescence-associated secretory phenotype (SASP). In patients affected by ADRs, the rate of aging process in increased, as well as the burden of senescent cells with SASP.
In this scenario, a better understanding of the molecular mechanisms that promote cellular senescence is of basic and clinical relevance. A number of mechanisms promoting senescence have been well characterized. Increasing evidence suggest that nuclear DNA fragility and a sub-functional DNA damage response (DDR) is associated with an increase release of nucleic acids in cytoplasm, including RNA:DNA hybrids. However, only few studies have tempted to assess the pro- or anti-inflammatory effects of this misplaced nucleic acid pool in different cellular models.
In this framework, we have analysed the cytoplasmic pool of misplaced nucleic acids in a model of human endothelial cells (HUVECs), in two prototypical stress conditions related to inflammaging, such as “replicative cellular senescence” and “hyperglycemic condition”.
A significant increased amount of misplaced nucleic acids was observed in the cytoplasm of senescent cells compared to the younger ones, and in young cells cultured for 1-week in hyperglycemic condition compared to young cells cultured in normoglycemic medium. The cytosolic pool of misplaced nucleic acids is composed of dsDNA, including micronuclei, bubbles and telomere sequences, dsRNA and hybrids. A reduced expression of RNaseH2, the enzyme involved in the degradation of RNA moiety of RNA:DNA hybrids was observed in senescent cells compared to the younger ones and in young cells treated with hyperglycemic medium. The amounts of mis incorporated ribonucleotides, biomarkers od genome instability, were inversely related to RNaseH2 expression level, suggesting that both “senescence” and “hyperglycemic condition” are associated with increased genomic instability.
Since the presence of nucleic acids in cytoplasm can activate a number of cytosolic receptors inducing the antiviral response, characterized by increased release of type 1 Interferon (IFN-1), we analysed cGAS/STING/IRF3 axis and IFN-1 expression in “senescence” and “hyperglycemic condition”. Surprisingly, a strong reduction of cGAS expression was observed in senescent cells in normo and hyperglycemic conditions, in association with the absence of IFN-1 modulation, whereas the expression of proinflammatory cytokines, such as IL-1beta, IL-6 and IL-8 was significantly increased. Overall, our results suggest an imbalance between antiviral and proinflammatory response in senescent cells and in young cells under hyperglycemic conditions.
Increasing evidence suggest that senescent cells have an enhanced susceptibility to viral infections. We hypothesized that such imbalance between antiviral and proinflammatory responses could be, almost in part, a direct consequence of their ability “to tolerate” a high cytosolic nucleic acids load.
Overall, our results pave the way to explain why old subjects, especially the elderly patients affected by diabetes, are more susceptible to adverse outcomes of infectious diseases.L'invecchiamento è caratterizzato da un graduale declino funzionale derivante da una complessa interazione tra fattori genetici e epigenetici insieme ad un'aumentata velocità di invecchiamento, riconosciuta come il fattore di rischio più importante per lo sviluppo delle malattie associate all'età più comuni (ARD). La ricerca sul processo di invecchiamento è attualmente focalizzata sulla comprensione dei meccanismi molecolari alla base delle caratteristiche legate all'età che accompagnano, da un lato, l'insorgenza di ARD e dall'altro, le possibilità di raggiungere un invecchiamento di successo. Uno stato pro-infiammatorio cronico, sistemico, di basso grado e legato all'età, chiamato "Inflammaging" è correlato allo sviluppo degli ARD. I due principali responsabili dell'inflammaging sono la stimolazione ripetuta del sistema immunitario nel tempo e l'aumento del numero di cellule senescenti. Le cellule senescenti sono in grado di modificare il microambiente acquisendo un fenotipo secretorio associato alla senescenza (SASP). Nei pazienti affetti da ADR, la velocità del processo d’invecchiamento è aumentato, così come il numero delle cellule senescenti con SASP. In questo scenario, una migliore comprensione dei meccanismi molecolari che promuovono la senescenza cellulare è di rilevanza di base e clinica.
Prove crescenti suggeriscono che la fragilità del DNA nucleare e una risposta sub-funzionale al danno al DNA (DDR) si associano a un aumento del rilascio di acidi nucleici nel citoplasma, inclusi gli ibridi RNA:DNA.
In questa cornice, abbiamo analizzato il pool di acidi nucleici rilasciati nel citoplasma in un modello di cellule endoteliali umane (HUVEC), in due condizioni di stress legate all'inflammaging, come la "senescenza replicativa cellulare " e la "condizione iperglicemica".
È stata osservata una quantità significativa di acidi nucleici nel citoplasma delle cellule senescenti rispetto a quelle più giovani e nelle cellule giovani coltivate per 1 settimana in condizioni iperglicemiche rispetto alle giovani cellule coltivate in mezzo normoglicemico. Il pool citosolico di acidi nucleici è composto da dsDNA, tra cui micronuclei, bubbles e sequenze telomeriche, dsRNA e ibridi. Una ridotta espressione di RNasi H2, l'enzima coinvolto nella degradazione della componente a RNA degli ibridi RNA:DNA è stato osservato nelle cellule senescenti rispetto a quelle più giovani e nelle cellule giovani trattate con mezzo iperglicemico. Le quantità di ribonucleotidi mal incorporati, biomarcatori dell’instabilità genomica, sono inversamente correlate al livello di espressione di RNasi H2, suggerendo che sia la "senescenza" che la "condizione iperglicemica" sono associate a una maggiore instabilità genomica.
Poiché la presenza di acidi nucleici nel citoplasma può attivare un certo numero di recettori citosolici che inducono la risposta antivirale, caratterizzata da un maggiore rilascio di interferone di tipo 1 (IFN-1), abbiamo analizzato l'asse cGAS/STING/IRF3 e l'espressione IFN-1 in "senescenza" e "condizione iperglicemica". Sorprendentemente, una forte riduzione dell'espressione di cGAS è stata osservata nelle cellule senescenti in condizioni normo e iperglicemiche, in associazione con l'assenza di modulazione di IFN-1, mentre l'espressione di citochine pro-infiammatorie, come IL-1 beta, IL-6 e IL-8 è significativamente aumentata. Nel complesso, i nostri risultati suggeriscono uno squilibrio tra la risposta antivirale e pro-infiammatoria nelle cellule senescenti e nelle cellule giovani in condizioni iperglicemiche.
Crescenti evidenze suggeriscono che le cellule senescenti hanno una maggiore suscettibilità alle infezioni virali. Abbiamo ipotizzato che tale squilibrio tra risposte antivirali e pro-infiammatorie potrebbe essere, almeno in parte, una conseguenza diretta della loro capacità di "tollerare" un elevato carico di acidi nucleici citosolici
Connecting vascular aging and frailty in Alzheimer's disease
No full textAging plays an important role in the etiology of the most common age-related diseases (ARDs), including Alzheimer's disease (AD). The increasing number of AD patients and the lack of disease-modifying drugs warranted intensive research to tackle the pathophysiological mechanisms underpinning AD development. Vascular aging/dysfunction is a common feature of almost all ARDs, including cardiovascular (CV) diseases, diabetes and AD. To this regard, interventions aimed at modifying CV outcomes are under extensive investigation for their pleiotropic role in ameliorating and slowing down cognitive impairment in middle-life and elderly individuals. Evidence from observational and clinical studies confirm the notion that the earlier the interventions are conducted, the most favorable are the effects on cognitive function. Therefore, epidemiological research should focus on the early detection of deviations from a healthy cognitive aging trajectory, through the stratification of adult individuals according to the rate of aging. Here, we review the interplay between vascular and cognitive dysfunctions associated with aging, to disentangle the complex mechanisms underpinning the development and progression of neurodegenerative disorders, with a specific focus on AD
The telomere world and aging: Analytical challenges and future perspectives
No full textTelomeres, the terminal nucleoprotein structures of eukaryotic chromosomes, play pleiotropic functions in cellular and organismal aging. Telomere length (TL) varies throughout life due to the influence of genetic factors and to a complex balancing between “shortening” and “elongation” signals. Telomerase, the only enzyme that can elongate a telomeric DNA chain, and telomeric repeat-containing RNA (TERRA), a long non-coding RNA involved in looping maintenance, play key roles in TL during life. Despite recent advances in the knowledge of TL, TERRA and telomerase activity (TA) biology and their measurement techniques, the experimental and theoretical issues involved raise a number of problems that should carefully be considered by researchers approaching the “telomere world”. The increasing use of such parameters – hailed as promising clinically relevant biomarkers – has failed to be paralleled by the development of automated and standardized measurement technology. Consequently, associating given TL values to specific pathological conditions involves on the one hand technological issues and on the other clinical-biological issues related to the planning of clinically relevant association studies. Addressing these issues would help avoid major biases in association studies involving TL and a number of outcomes, especially those focusing on psychological and bio-behavioral variables. The main challenge in telomere research is the development of accurate and reliable measurement methods to achieve simple and sensitive TL, TERRA, and TA detection. The discovery of the localization of telomeres and TERRA in cellular and extracellular compartments had added an additional layer of complexity to the measurement of these age-related biomarkers. Since combined analysis of TL, TERRA and TA may well provide more exhaustive clinical information than a single parameter, we feel it is important for researchers in the various fields to become familiar with their most common measurement techniques and to be aware of the respective merits and drawbacks of these approache
Circulating biomarkers of inflammaging as potential biomarkers of COVID-19 severe outcomes
No full text: The COVID-19 pandemic caused by SARS-CoV-2 infection has been of unprecedented clinical and socio-economic worldwide relevance. The case fatality rate for COVID-19 grows exponentially with age and the presence of comorbidities. In elderly patients, COVID-19 manifests predominantly as a systemic disease associated with immunological, inflammatory, and procoagulant responses. Timely diagnosis and risk stratification are crucial steps to define appropriate therapies and reduce mortality, especially in elderly patients. Chronically and systemically activated innate immune responses and impaired antiviral responses have been recognized as the results of a progressive remodeling of the immune system during aging, which can be described by the words 'immunosenescence' and 'inflammaging'. These age-related features of the immune system were highlighted in patients affected by COVID-19 with the poorest clinical outcomes, suggesting that the mechanisms underpinning immunosenescence and inflammaging could be relevant for COVID-19 pathogenesis and progression. Increasing evidence suggests that senescent myeloid and endothelial cells are characterized by the acquisition of a senescence-associated proinflammatory phenotype (SASP), which is considered as the main culprit of both immunosenescence and inflammaging. Here, we reviewed this evidence and highlighted several circulating biomarkers of inflammaging that could provide additional prognostic information to stratify COVID-19 patients based on the risk of severe outcomes
Zingiber officinale Roscoe Rhizome Extract Exerts Senomorphic and Anti-Inflammatory Activities on Human Endothelial Cells
Get PDFAging is related to a low-grade and sterile inflammation called inflammaging, recognized as the main risk factor for age-related disease (ARD) development. Inflammaging is fostered by the repeated activation of immune cells, as well as by the accumulation of senescent cells. Recently, a number of natural compounds have gained attention to be tested as anti-aging therapies, based on their anti-inflammatory activity and/or ability to reduce the pro-inflammatory secretome of senescent cells (senomorphyc activity). Here, we investigated the anti-inflammatory and senomorphic properties of an Asian-native Zingiber officinale Roscoe extract (ZOE), commonly consumed as a food spice and herbal medicine. We employed two models of primary endothelial cells (HUVECs), such as the replicative-senescence and LPS-induced response, to investigate the anti-inflammatory/senomorphic effect of ZOE, and one cellular model of neuroinflammation, i.e., immortalized murine microglial cells (BV2). First, we found that the ZOE treatment induced the inhibition of NF-kB activation in BV2 cells. Among the constituents of ZOE, we showed that the terpenoid-enriched fraction (ZTE) was the component able to counteract the phosphorylation of NF-kB(p65), while 6-gingerol (GIN) and 6-shogaol (SHO) did not produce any significant effect. Further, we observed that the treatment with 10 µg/mL of ZOE exerted anti-inflammatory activity on LPS-stimulated young (y)HUVEC and senomorphyc activity on replicative senescent (s)HUVEC, significantly reducing the expression levels of IL-1β, TNF -α, IL-8, MCP-1, and ICAM-1. Moreover, the ZTE treatment was able to significantly reduce the IL-8 levels secreted in the medium of both LPS-stimulated yHUVEC and sHUVEC. Overall, our data suggest a potential protective role of ZOE on neuroinflammation and endothelial inflammation/activation, thus suggesting its potential relevance in delaying/postponing ARD development and progression, characterized by endothelial dysfunction
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Sex/gender-related differences in inflammaging
Get PDFGeroscience puts mechanisms of aging as a driver of the most common age-related diseases and dysfunctions. Under this perspective, addressing the basic mechanisms of aging will produce a better understanding than addressing each disease pathophysiology individually. Worldwide, despite greater functional impairment, life expectancy is higher in women than in men. Gender differences in the prevalence of multimorbidity lead mandatory to the understanding of the mechanisms underlying gender-related differences in multimorbidity patterns and disability-free life expectancy. Extensive literature suggested that inflammaging is at the crossroad of aging and age-related diseases. In this review, we highlight the main evidence on sex/gender differences in the mechanisms that foster inflammaging, i.e. the age-dependent triggering of innate immunity, modifications of adaptive immunity, and accrual of senescent cells, underpinning some biomarkers of inflammaging that show sex-related differences. In the framework of the “gender medicine perspective”, we will also discuss how sex/ gender differences in inflammaging can affect sex differences in COVID-19 severe outcomes
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