Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in ...age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.
Background
Coinciding with other chronic comorbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of ...age‐related pathologies, where they promote “non‐microbial” inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age.
Methods
Alveolar bone samples were obtained from young (6 months) and old (20 to 22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte‐enriched fractions were used to characterize the age‐related senescence‐associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS).
Results
Increased senescence‐associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin‐6 (IL6), IL17, IGFBP4, and MMP13 were significantly upregulated with aging in osteocyte‐enriched samples. Interestingly, SCM potentiated the LPS‐induced expression of IL1α, IL1β, and IL6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190.
Conclusions
Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell‐intrinsic response to DNA damage, and a host‐related mechanism associated with aging that could potentiate inflammation induced by bacterial components.
Peer review practices differ substantially between journals and disciplines. This study presents the results of a survey of 322 editors of journals in ecology, economics, medicine, physics and ...psychology. We found that 49% of the journals surveyed checked all manuscripts for plagiarism, that 61% allowed authors to recommend both for and against specific reviewers, and that less than 6% used a form of open peer review. Most journals did not have an official policy on altering reports from reviewers, but 91% of editors identified at least one situation in which it was appropriate for an editor to alter a report. Editors were also asked for their views on five issues related to publication ethics. A majority expressed support for co-reviewing, reviewers requesting access to data, reviewers recommending citations to their work, editors publishing in their own journals, and replication studies. Our results provide a window into what is largely an opaque aspect of the scientific process. We hope the findings will inform the debate about the role and transparency of peer review in scholarly publishing.
Cellular senescence is associated with inflammation and extracellular matrix tissue remodeling through the secretion of proteins termed the senescence-associated secretory phenotype (SASP). Although ...osteocyte senescence in older individuals in the skeleton is well recognized, whether young alveolar osteocytes can also become senescent is unknown. This is potentially important in the context of periodontal disease, which is an inflammatory condition caused by a gradual change from symbiotic to pathogenic oral microflora that can lead to tooth loss. Our aim was to identify whether senescent osteocytes accumulate in young alveolar bone and whether bacterial-derived lipopolysaccharide (LPS) can influence cellular senescence in alveolar bone. An osteocyte-enriched cell population isolated from alveolar bone expressed increased levels of the known senescence marker p16Ink4a, as well as select SASP markers known to be implicated alveolar bone resorption (Icam1, Il6, Il17, Mmp13 and Tnfα), compared to ramus control cells. Increased senescence of alveolar bone osteocytes was also observed in vivo using the senescence-associated distension of satellites (SADS) assay and increased γH2AX, a marker of DNA damage associated with senescent cells. To approximate a bacterial infection in vitro, alveolar osteocytes were treated with LPS. We found increased expression of various senescence and SASP markers, increased γH2AX staining, increased SA-β-Gal activity and the redistribution of F-actin leading to a larger and flattened cell morphology, all hallmarks of cellular senescence. In conclusion, our data suggests a model whereby bacterial-derived LPS stimulates premature alveolar osteocyte senescence, which in combination with the resultant SASP, could potentially contribute to the onset of alveolar bone loss.
•Premature osteocyte senescence is a host response to bacterial infection and a mechanism implicated in alveolar bone loss.•Increased numbers of dysfunctional senescent osteocytes in alveolar bone could jeopardize tissue homeostasis.•Alveolar osteocytes may be more susceptible to LPS-induced stress due to their proximity to periodontal bacterial infection.•Osteocytes secreted factors represent a “non-microbial” source of pro-inflammatory factors that exacerbate inflammation.•Premature osteocyte accumulation may be a novel mechanism implicated in the pathogenesis of early-onset periodontitis.
To synthesise research investigating data and code sharing in medicine and health to establish an accurate representation of the prevalence of sharing, how this frequency has changed over time, and ...what factors influence availability.
Systematic review with meta-analysis of individual participant data.
Ovid Medline, Ovid Embase, and the preprint servers medRxiv, bioRxiv, and MetaArXiv were searched from inception to 1 July 2021. Forward citation searches were also performed on 30 August 2022.
Meta-research studies that investigated data or code sharing across a sample of scientific articles presenting original medical and health research were identified. Two authors screened records, assessed the risk of bias, and extracted summary data from study reports when individual participant data could not be retrieved. Key outcomes of interest were the prevalence of statements that declared that data or code were publicly or privately available (declared availability) and the success rates of retrieving these products (actual availability). The associations between data and code availability and several factors (eg, journal policy, type of data, trial design, and human participants) were also examined. A two stage approach to meta-analysis of individual participant data was performed, with proportions and risk ratios pooled with the Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis.
The review included 105 meta-research studies examining 2 121 580 articles across 31 specialties. Eligible studies examined a median of 195 primary articles (interquartile range 113-475), with a median publication year of 2015 (interquartile range 2012-2018). Only eight studies (8%) were classified as having a low risk of bias. Meta-analyses showed a prevalence of declared and actual public data availability of 8% (95% confidence interval 5% to 11%) and 2% (1% to 3%), respectively, between 2016 and 2021. For public code sharing, both the prevalence of declared and actual availability were estimated to be <0.5% since 2016. Meta-regressions indicated that only declared public data sharing prevalence estimates have increased over time. Compliance with mandatory data sharing policies ranged from 0% to 100% across journals and varied by type of data. In contrast, success in privately obtaining data and code from authors historically ranged between 0% and 37% and 0% and 23%, respectively.
The review found that public code sharing was persistently low across medical research. Declarations of data sharing were also low, increasing over time, but did not always correspond to actual sharing of data. The effectiveness of mandatory data sharing policies varied substantially by journal and type of data, a finding that might be informative for policy makers when designing policies and allocating resources to audit compliance.
Open Science Framework doi:10.17605/OSF.IO/7SX8U.
Primary central nervous system lymphoma (PCNSL) is primarily treated with combination chemotherapy, while whole-brain radiotherapy (WBRT) can be used as consolidative treatment or as a salvage option ...for central nervous system (CNS) relapse. We investigated whether fractionated stereotactic radiosurgery (fSRS) could replace WBRT in cases where patients had poor performance status or minimal disease at the time of consolidation, to spare patients the adverse effects of WBRT. We retrospectively identified 10 patients who completed 14 courses of fSRS for PCNSL or for CNS relapse of systemic lymphoma. Of 14 fSRS treatments, there were 10 distant brain recurrences among 6 patients, occurring on average 13.6 months after fSRS. A total of 4 of the 10 recurrences were treated with further fSRS, and 4 were treated with WBRT. There was one late in-field recurrence after both fSRS and WBRT, which occurred 27 months after fSRS. The median survival after fSRS was 36 months, and side effects after fSRS were minimal. This case series represents a potential treatment option for patients with CNS lymphoma, for whom WBRT is indicated but where the toxic effects of this treatment would be prohibitive.
Demodex mites are commensal parasites of hair follicles (HFs). Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction, and aging, but mechanisms ...restricting Demodex outgrowth are not defined. Here, we show that control of mite HF colonization in mice required group 2 innate lymphoid cells (ILC2s), interleukin-13 (IL-13), and its receptor, IL-4Ra-IL-13Ra1. HF-associated ILC2s elaborated IL-13 that attenuated HFs and epithelial proliferation at anagen onset; in their absence, Demodex colonization led to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammation, leading to the loss of barrier function and HF exhaustion. Humans with rhinophymatous acne rosacea, an inflammatory condition associated with Demodex, had increased HF inflammation with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a key role for skin ILC2s and IL-13, which comprise an immune checkpoint that sustains cutaneous integrity and restricts pathologic infestation by colonizing HF mites.
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•Type 2 innate immunity is critical for normal commensalism with Demodex•In the absence of type 2 immunity, Demodex causes aberrant inflammation•IL-13 from ILC2s is coupled to the hair cycle and restrains stem cell proliferation•Decreased type 2 cytokine expression is observed in patients with rhinophyma
Type 2 cytokines are well recognized for their role in mediating allergic pathologies in skin, but their role in normal skin physiology is unclear. Ricardo-Gonzalez et al. reveal that type 2 immunity restrains skin inflammation in response to injury that is necessary to control hair follicle commensalism by Demodex mites.
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