Agings
Abstract
It is currently thought that ultraviolet B (UVB) radiation drives photoaging of the skin primarily by generating reactive oxygen species (ROS). In this model, ROS purportedly activates AP-1 to upregulate matrix metalloproteinases (MMPs) 1, 3, and 9, which then degrade collagen and other extracellular matrix components to produce wrinkles. However, these MMPs are expressed at relatively low levels and correlate poorly with wrinkles, suggesting that another mechanism distinct from ROS and MMP1/3/9 may be more directly associated with photoaging. Here we show that MMP2, which degrades type IV collagen, is abundantly expressed in human skin, increases with age in sun-exposed skin, and correlates robustly with aryl hydrocarbon receptor (AhR), a transcription factor directly activated by UV-generated photometabolites. Through mechanistic studies with HaCaT keratinocytes, we found that AhR, SP1, and other pathways associated with DNA damage are required for the induction of both MMP2 and MMP11 (another MMP implicated in photoaging), but not MMP1/3. Lastly, we found that topical treatment with AhR antagonists vitamin B12 and folic acid ameliorated UVB-induced wrinkle formation in mice while dampening MMP2 expression in the skin. These results directly implicate DNA damage in photoaging and reveal AhR as a potential target for preventing wrinkles.
Authors
Daniel J. Kim, Akiko Iwasaki, Anna L. Chien, Sewon Kang
Abstract
Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by the accumulation of myofibroblasts and progressive lung scarring. To identify transcriptional gene programs driving persistent lung fibrosis in aging, we performed RNA-seq on lung fibroblasts isolated from young and aged mice during the early resolution phase post-bleomycin injury. We discovered that relative to injured young fibroblasts, injured aged fibroblasts exhibited a pro-fibrotic state characterized by elevated expression of genes implicated in inflammation, matrix remodeling, and cell survival. We identified pro-viral integration site of Moloney murine leukemia virus 1 (PIM1) and its target Nuclear Factor of Activated T Cells-1 (NFATc1) as putative drivers of the sustained pro-fibrotic gene signatures in injured aged fibroblasts. PIM1 and NFATc1 transcripts were enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was abundant in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts in vitro potentiated their fibrogenic activation in a NFATc1-dependent manner. Pharmacological inhibition of PIM1 attenuated IPF fibroblast activation and sensitized them to apoptotic stimuli. Inhibition of PIM1 signaling in IPF lung explants ex vivo inhibited pro-survival gene expression and collagen secretion, suggesting that targeting this pathway may represent a therapeutic strategy to block IPF progression.
Authors
Tho X. Pham, Jisu Lee, Jiazhen Guan, Nunzia Caporarello, Jeffrey A. Meridew, Dakota L. Jones, Qi Tan, Steven K. Huang, Daniel J. Tschumperlin, Giovanni Ligresti
Abstract
Following myocardial infarction (MI), elderly patients have a poorer prognosis which may belinked to increased coronary microvessel susceptibility to injury. Interleukin-36 (IL-36), anewly discovered pro-inflammatory member of the IL-1 superfamily, may mediate this injurybut its role in the injured heart is currently not known. We firstly demonstrated the presence of IL-36(α/β) and its receptor (IL-36R) in ischaemia-reperfusion (IR) injured mouse hearts and,interestingly, noted that expression of both increased with ageing. An intravital modelfor imaging the adult and aged IR injured beating heart in real-time in vivo was used todemonstrate heightened basal and injury-induced neutrophil recruitment, and poorer bloodflow, in the aged coronary microcirculation when compared to adult hearts. An IL-36Rantagonist (IL-36Ra) significantly decreased neutrophil recruitment, improved blood flow andreduced infarct size in both adult and aged mice. This may be mechanistically explained byattenuated endothelial oxidative damage and VCAM-1 expression in IL-36Ra treated mice.Our findings of an enhanced age-related coronary microcirculatory dysfunction inreperfused hearts may explain the poorer outcomes in elderly patients following MI. Sincetargeting the IL-36/IL-36R pathway was vasculoprotective in aged hearts, it may potentially be a therapy for treating MI in the elderly.
Authors
Juma El-Awaisi, Dean P.J. Kavanagh, Marco R. Rink, Chris J. Weston, Nigel E. Drury, Neena Kalia
Abstract
BACKGROUND. Tight relationships between sleep quality, cognition and amyloid-beta (Aβ) accumulation, a hallmark of Alzheimer’s disease (AD) neuropathology, emerge in the literature. Sleep arousals become more prevalent with ageing and are considered to reflect poorer sleep quality. Yet, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established. METHODS. We recorded undisturbed night-time sleep with EEG in 101 healthy individuals in late midlife (50-70y), devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M-) and sleep stage transition (T+/T-). We assessed cortical Aβ burden over earliest affected regions via PET imaging, and cognition via extensive neuropsychological testing. RESULTS. Arousal types differed in their oscillatory composition in theta and beta EEG bands. Furthermore, T+M- arousals, which interrupt sleep continuity, were positively linked to Aβ burden (p=.0053, R²β*=0.08). By contrast, more prevalent T-M+ arousals, upholding sleep continuity, were associated with lower Aβ burden (p=.0003, R²β*=0.13), and better cognition, particularly over the attentional domain (p<.05, R²β*≥0.04). CONCLUSION. Contrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep. This warrants re-evaluation of age-related sleep changes and suggests that spontaneous arousals could constitute a marker of favourable brain and cognitive health trajectories. TRIAL REGISTRATION. EudraCT 2016-001436-35. FUNDING. This work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, FRSM 3.4516.11, Belgium), Actions de Recherche Concertées (ARC SLEEPDEM 17/27-09) of the Fédération Wallonie-Bruxelles, University of Liège (ULiège), Fondation Simone et Pierre Clerdent, European Regional Development Fund (ERDF, Radiomed Project). [18F]Flutemetamol doses were provided and cost covered by GE Healthcare Ltd (Little Chalfont, UK) as part of an investigator sponsored study (ISS290) agreement. This agreement had no influence on the protocol and results of the study reported here. M.V.E., C.B., F.C., C.P., and G.V. are/were supported by the F.R.S.-FNRS Belgium. C. B., P. B. and M. B. are owners of Physip, the company that analysed the EEG data as part of a collaboration. This ownership and the collaboration had no impact on the design, data acquisition and interpretations of the findings.
Authors
Daphne O. Chylinski, Maxime Van Egroo, Justinas Narbutas, Martin Grignard, Ekaterina Koshmanova, Christian Berthomier, Pierre Berthomier, Marie Brandewinder, Eric Salmon, Mohamed Ali Bahri, Christine Bastin, Fabienne Collette, Christophe Phillips, Pierre Maquet, Vincenzo Muto, Gilles Vandewalle
Abstract
Osteoarthritis is the most prevalent joint disease worldwide and a leading source of pain and disability. To date, this disease lacks curative treatment as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identify transcription factors and networks that regulate DOT1L gene expression using a novel bioinformatics pipeline. Thereby, we unravel an undiscovered link between the hypoxia pathway and DOT1L. We provide unprecedented evidence that hypoxia enhances DOT1L expression and H3K79 methylation via Hypoxia-inducible factor-1 alpha (HIF1A). Importantly, we demonstrate that DOT1L contributes to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restores DOT1L function and stalls disease progression. Collectively, our data unravel a novel molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.
Authors
Astrid De Roover, Ana Escribano Núñez, Frederique M.F. Cornelis, Chahrazad Cherifi, Leire Casas-Fraile, An Sermon, Frederic Cailotto, Rik J. Lories, Silvia Monteagudo
Abstract
BACKGROUND. Neighborhood-level socioeconomic disadvantage has wide-ranging impacts on health outcomes, particularly in older adults. Although indices of disadvantage are a widely used tool, research conducted to date has not codified a set of standard variables that should be included in these indices for the US. The objective of this study was to conduct a systematic review of literature describing the construction of geographic indices of neighborhood-level disadvantage and to summarize and distill the key variables included in these indices. We also sought to demonstrate the utility of these indices for understanding neighborhood-level disadvantage in older adults. METHODS. We conducted a systematic review of existing indices in the English-language literature. RESULTS. We identified 6,021 articles, of which 130 met final study inclusion criteria. Our review identified seven core domains that existed across the surveyed papers, including: income, education, housing, employment, neighborhood structure, demographic makeup and health. While not universally present, the most prevalent variables included in these indices were education and employment. CONCLUSION. Identifying these seven core domains is a key finding of this review. These domains should be considered for inclusion in future neighborhood-level disadvantage indices with at least 5 domains recommended to improve the strength of the resulting index. Targeting specific domains offers a path forward towards the construction of a new US-specific index of neighborhood disadvantage with health policy applications. Such an index will be especially useful for characterizing the lifecourse impact of lived disadvantage in older adults.
Authors
William R. Buckingham, Lauren Bishop, Christopher Hooper-Lane, Brittany Anderson, Jessica Wolfson, Stephanie V. Shelton, Amy J.H. Kind
Abstract
BACKGROUND The incidence of burn injuries in older patients is dramatically increasing as the population of older people grows. Despite the increased demand for elderly burn care, the mechanisms that mediate increased morbidity and mortality in older trauma patients are unknown. We recently showed that a burn injury invokes white adipose tissue browning that leads to a substantially increased hypermetabolic response associated with poor outcomes. Therefore, the aim of this study was to determine the effect of age on the metabolic adipose response of browning after a burn injury.METHOD One hundred and seventy patients with burn injury admitted to the Ross Tilley Burn Centre were prospectively enrolled and grouped by age as older (≥50 years) and young (≤35 years). Adipose tissue and sera were collected and analyzed for browning markers and metabolic state via histology, gene expression, and resting energy expenditure assays.RESULTS We found that older patients with burn injury lacked the adipose browning response, as they showed significant reductions in uncoupling protein 1 (UCP1) expression. This failure of the browning response was associated with reduced whole-body metabolism and decreased survival in older patients with burn injury. Mechanistically, we found that the adipose of both aged patients after burn trauma and aged mice after a burn showed impairments in macrophage infiltration and IL-6, key immunological regulators of the browning process after a severe trauma.CONCLUSION Targeting pathways that activate the browning response represents a potential therapeutic approach to improve outcomes after burn trauma for elderly patients.FUNDING NIH (R01-GM087285-01), Canadian Institutes of Health Research (grant no. 123336), and Canada Foundation for Innovation Leaders Opportunity Fund (no. 25407).
Authors
Abdikarim Abdullahi, Carly M. Knuth, Christopher Auger, Thibacg Sivayoganathan, Alexandra Parousis, Marc G. Jeschke
Abstract
Degenerative cervical myelopathy (DCM) is the most common cause of nontraumatic spinal cord injury in adults worldwide. Surgical decompression is generally effective in improving neurological outcomes and halting progression of myelopathic deterioration. However, a subset of patients experience suboptimal neurological outcomes. Given the emerging evidence that apolipoprotein E4 (ApoE4) allelic status influences neurodegenerative conditions, we examined whether the presence of the ApoE4 allele may account for the clinical heterogeneity of treatment outcomes in patients with DCM. Our results demonstrate that human ApoE4+ DCM patients have a significantly lower extent of improvement after decompression surgery. Functional analysis of our DCM mouse model in targeted-replacement mice expressing human ApoE4 revealed delayed gait recovery, forelimb grip strength, and hind limb mechanical sensitivity after decompression surgery, compared with their ApoE3 counterparts. This was accompanied by an exacerbated proinflammatory response resulting in higher concentrations of TNF-α, IL-6, CCL3, and CXCL9. At the site of injury, there was a significant decrease in gray matter area, an increase in the activation of microglia/macrophages, and increased astrogliosis after decompression surgery in the ApoE4 mice. Our study is the first to our knowledge to investigate the pathophysiological underpinnings of ApoE4 in DCM, which suggests a possible personalized medicine approach for the treatment of DCM in ApoE4 carriers.
Authors
Alexa Desimone, James Hong, Sydney T. Brockie, Wenru Yu, Alex M. Laliberte, Michael G. Fehlings
Abstract
Aging is associated with chronic oxidative stress and inflammation that impact the tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here we demonstrate that the expression of MG53 is reduced in failing human heart and aging mouse heart, concomitant with elevated NFκB activation. We evaluate the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements reveal beneficial effects of rhMG53 treatment in improving heart function of aging mice. Biochemical and histological studies demonstrate the cardioprotective effects of rhMG53 are linked to suppression of NFκB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administrations of rhMG53 in aged mice do not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
Authors
Xiaoliang Wang, Xiuchun Li, Hannah Ong, Tao Tan, Ki Ho Park, Zehua Bian, Xunchang Zou, Erin Haggard, Paul M. Janssen, Robert E. Merritt, Timothy M. Pawlik, Bryan A. Whitson, Nahush A. Mokadam, Lei Cao, Hua Zhu, Chuanxi Cai, Jianjie Ma
Abstract
Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers of senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity of these senescent cells remain unclear, and tools to characterize context-specific cellular senescence in human lung are lacking. We observed that the senescent marker p16 is predominantly localized to bronchiolized epithelial structures in scarred regions of IPF and systemic sclerosis associated interstitial lung disease ILD (SSc-ILD) lung tissue, overlapping with the basal epithelial markers Keratin 5 and Keratin 17. Using in vitro models, we derived transcriptional signatures of senescence programming specific to different types of lung epithelial cells, and interrogated these signatures in a single-cell RNA-seq data set derived from control, IPF, and SSc-ILD lung tissue. We identified a population of basal epithelial cells defined by, and enriched for, markers of cellular senescence, and identified candidate markers specific to senescent basal epithelial cells in ILD that can enable future functional studies. Notably, gene expression of these cells significantly overlaps with terminally differentiating cells in stratified epithelia, where it is driven by p53 activation as part of the senescence program.
Authors
Daryle J. DePianto, Jason A. Vander Heiden, Katrina B. Morshead, Kai-Hui Sun, Zora Modrusan, Grace Teng, Paul J. Wolters, Joseph R. Arron
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