@article{BugaMargaritescuScholzetal.2014, author = {Buga, Ana Maria and Margaritescu, Claudiu and Scholz, Claus J{\"u}rgen and Radu, Eugen and Zelenak, Christine and Popa-Wagner, Aurel}, title = {Transcriptomics of Post-Stroke Angiogenesis in the Aged Brain}, series = {Frontiers in Aging Neuroscience}, volume = {6}, journal = {Frontiers in Aging Neuroscience}, number = {44}, doi = {10.3389/fnagi.2014.00044}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120700}, year = {2014}, abstract = {Despite the obvious clinical significance of post-stroke angiogenesis in aged subjects, a detailed transcriptomic analysis of post-stroke angiogenesis has not yet been undertaken in an aged experimental model. In this study, by combining stroke transcriptomics with immunohistochemistry in aged rats and post-stroke patients, we sought to identify an age-specific gene expression pattern that may characterize the angiogenic process after stroke. We found that both young and old infarcted rats initiated vigorous angiogenesis. However, the young rats had a higher vascular density by day 14 post-stroke. "New-for-stroke" genes that were linked to the increased vasculature density in young animals included Angpt2, Angptl2, Angptl4, Cib1, Ccr2, Col4a2, Cxcl1, Lef1, Hhex, Lamc1, Nid2, Pcam1, Plod2, Runx3, Scpep1, S100a4, Tgfbi, and Wnt4, which are required for sprouting angiogenesis, reconstruction of the basal lamina (BL), and the resolution phase. The vast majority of genes involved in sprouting angiogenesis (Angpt2, Angptl4, Cib1, Col8a1, Nrp1, Pcam1, Pttg1ip, Rac2, Runx1, Tnp4, Wnt4); reconstruction of a new BL (Col4a2, Lamc1, Plod2); or tube formation and maturation (Angpt1, Gpc3, Igfbp7, Sparc, Tie2, Tnfsf10), had however, a delayed upregulation in the aged rats. The angiogenic response in aged rats was further diminished by the persistent upregulation of "inflammatory" genes (Cxcl12, Mmp8, Mmp12, Mmp14, Mpeg1, Tnfrsf1a, Tnfrsf1b) and vigorous expression of genes required for the buildup of the fibrotic scar (Cthrc1, Il6ra, Il13ar1, Il18, Mmp2, Rassf4, Tgfb1, Tgfbr2, Timp1). Beyond this barrier, angiogenesis in the aged brains was similar to that in young brains. We also found that the aged human brain is capable of mounting a vigorous angiogenic response after stroke, which most likely reflects the remaining brain plasticity of the aged brain.}, language = {en} } @article{CaliskanCrouchGiddinsetal.2022, author = {Caliskan, Aylin and Crouch, Samantha A. W. and Giddins, Sara and Dandekar, Thomas and Dangwal, Seema}, title = {Progeria and aging — Omics based comparative analysis}, series = {Biomedicines}, volume = {10}, journal = {Biomedicines}, number = {10}, issn = {2227-9059}, doi = {10.3390/biomedicines10102440}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289868}, year = {2022}, abstract = {Since ancient times aging has also been regarded as a disease, and humankind has always strived to extend the natural lifespan. Analyzing the genes involved in aging and disease allows for finding important indicators and biological markers for pathologies and possible therapeutic targets. An example of the use of omics technologies is the research regarding aging and the rare and fatal premature aging syndrome progeria (Hutchinson-Gilford progeria syndrome, HGPS). In our study, we focused on the in silico analysis of differentially expressed genes (DEGs) in progeria and aging, using a publicly available RNA-Seq dataset (GEO dataset GSE113957) and a variety of bioinformatics tools. Despite the GSE113957 RNA-Seq dataset being well-known and frequently analyzed, the RNA-Seq data shared by Fleischer et al. is far from exhausted and reusing and repurposing the data still reveals new insights. By analyzing the literature citing the use of the dataset and subsequently conducting a comparative analysis comparing the RNA-Seq data analyses of different subsets of the dataset (healthy children, nonagenarians and progeria patients), we identified several genes involved in both natural aging and progeria (KRT8, KRT18, ACKR4, CCL2, UCP2, ADAMTS15, ACTN4P1, WNT16, IGFBP2). Further analyzing these genes and the pathways involved indicated their possible roles in aging, suggesting the need for further in vitro and in vivo research. In this paper, we (1) compare "normal aging" (nonagenarians vs. healthy children) and progeria (HGPS patients vs. healthy children), (2) enlist genes possibly involved in both the natural aging process and progeria, including the first mention of IGFBP2 in progeria, (3) predict miRNAs and interactomes for WNT16 (hsa-mir-181a-5p), UCP2 (hsa-mir-26a-5p and hsa-mir-124-3p), and IGFBP2 (hsa-mir-124-3p, hsa-mir-126-3p, and hsa-mir-27b-3p), (4) demonstrate the compatibility of well-established R packages for RNA-Seq analysis for researchers interested but not yet familiar with this kind of analysis, and (5) present comparative proteomics analyses to show an association between our RNA-Seq data analyses and corresponding changes in protein expression.}, language = {en} } @article{ClineCostaNunesCespuglioetal.2015, author = {Cline, Brandon H. and Costa-Nunes, Joao P. and Cespuglio, Raymond and Markova, Natalyia and Santos, Ana I. and Bukhman, Yury V. and Kubatiev, Aslan and Steinbusch, Harry W. M. and Lesch, Klaus-Peter and Strekalova, Tatyana}, title = {Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression}, series = {Frontiers in Behavioral Neuroscience}, volume = {9}, journal = {Frontiers in Behavioral Neuroscience}, number = {37}, doi = {10.3389/fnbeh.2015.00037}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143992}, year = {2015}, abstract = {Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naive DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naive animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.}, language = {en} } @article{HaringPettingerBeaetal.2013, author = {Haring, Bernhard and Pettinger, Mary and Bea, Jennifer W. and Wactawski-Wende, Jean and Carnahan, Ryan M. and Ockene, Judith K. and Wyler von Ballmoos, Moritz and Wallace, Robert B. and Wassertheil-Smoller, Sylvia}, title = {Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative}, series = {BMC Geriatrics}, journal = {BMC Geriatrics}, doi = {10.1186/1471-2318-13-38}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-95960}, year = {2013}, abstract = {Background Laxatives are among the most widely used over-the-counter medications in the United States but studies examining their potential hazardous side effects are sparse. Associations between laxative use and risk for fractures and change in bone mineral density [BMD] have not previously been investigated. Methods This prospective analysis included 161,808 postmenopausal women (8907 users and 151,497 nonusers of laxatives) enrolled in the WHI Observational Study and Clinical Trials. Women were recruited from October 1, 1993, to December 31, 1998, at 40 clinical centers in the United States and were eligible if they were 50 to 79 years old and were postmenopausal at the time of enrollment. Medication inventories were obtained during in-person interviews at baseline and at the 3-year follow-up visit on everyone. Data on self-reported falls (≥2), fractures (hip and total fractures) were used. BMD was determined at baseline and year 3 at 3 of the 40 clinical centers of the WHI. Results Age-adjusted rates of hip fractures and total fractures, but not for falls were similar between laxative users and non-users regardless of duration of laxative use. The multivariate-adjusted hazard ratios for any laxative use were 1.06 (95\% confidence interval [CI], 1.03-1.10) for falls, 1.02 (95\% CI, 0.85-1.22) for hip fractures and 1.01 (95\% CI, 0.96-1.07) for total fractures. The BMD levels did not statistically differ between laxative users and nonusers at any skeletal site after 3-years intake. Conclusion These findings support a modest association between laxative use and increase in the risk of falls but not for fractures. Its use did not decrease bone mineral density levels in postmenopausal women. Maintaining physical functioning, and providing adequate treatment of comorbidities that predispose individuals for falls should be considered as first measures to avoid potential negative consequences associated with laxative use.}, language = {en} } @article{HetzAcikgoezMolletal.2014, author = {Hetz, Susan and Acikgoez, Ali and Moll, Corinna and Jahnke, Heinz-Georg and Robitzki, Andrea A. and Metzger, Roman and Metzger, Marco}, title = {Age-related gene expression analysis in enteric ganglia of human colon after laser microdissection}, series = {Frontiers in Aging Neuroscience}, volume = {6}, journal = {Frontiers in Aging Neuroscience}, issn = {1663-4365}, doi = {10.3389/fnagi.2014.00276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118308}, pages = {276}, year = {2014}, abstract = {The enteric nervous system (ENS) poses the intrinsic innervation of the gastrointestinal tract and plays a critical role for all stages of postnatal life. There is increasing scientific and clinical interest in acquired or age-related gastrointestinal dysfunctions that can be manifested in diseases such as gut constipation or fecal incontinence. In this study, we sought to analyze age-dependent changes in the gene expression profile of the human ENS, particularly in the myenteric plexus. Therefore, we used the laser microdissection technique which has been proven as a feasible tool to analyze distinct cell populations within heterogeneously composed tissues. Full biopsy gut samples were prepared from children (4-12 months), middle aged (48-58 years) and aged donors (70-95 years). Cryosections were histologically stained with H\&E, the ganglia of the myenteric plexus identified and RNA isolated using laser microdissection technique. Quantitative PCR was performed for selected neural genes, neurotransmitters and receptors. Data were confirmed on protein level using NADPH-diaphorase staining and immunohistochemistry. As result, we demonstrate age-associated alterations in site-specific gene expression pattern of the ENS. Thus, in the adult and aged distal parts of the colon a marked decrease in relative gene expression of neural key genes like NGFR, RET, NOS1 and a concurrent increase of CHAT were observed. Further, we detected notable regional differences of RET, CHAT, TH, and S100B comparing gene expression in aged proximal and distal colon. Interestingly, markers indicating cellular senescence or oxidative stress (SNCA, CASP3, CAT, SOD2, and TERT) were largely unchanged within the ENS. For the first time, our study also describes the age-dependent expression pattern of all major sodium channels within the ENS. Our results are in line with previous studies showing spatio-temporal differences within the mammalian ENS.}, language = {en} } @article{KemmlerKohlFroehlichetal.2020, author = {Kemmler, Wolfgang and Kohl, Matthias and Fr{\"o}hlich, Michael and Jakob, Franz and Engelke, Klaus and von Stengel, Simon and Schoene, Daniel}, title = {Effects of High-Intensity Resistance Training on Osteopenia and Sarcopenia Parameters in Older Men with Osteosarcopenia—One-Year Results of the Randomized Controlled Franconian Osteopenia and Sarcopenia Trial (FrOST)}, series = {Journal of Bone and Mineral Research}, volume = {35}, journal = {Journal of Bone and Mineral Research}, number = {9}, doi = {10.1002/jbmr.4027}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214609}, pages = {1634 -- 1644}, year = {2020}, abstract = {Dynamic resistance exercise (DRT) might be the most promising agent for fighting sarcopenia in older people. However, the positive effect of DRT on osteopenia/osteoporosis in men has still to be confirmed. To evaluate the effect of low-volume/high-intensity (HIT)-DRT on bone mineral density (BMD) and skeletal muscle mass index (SMI) in men with osteosarcopenia, we initiated the Franconian Osteopenia and Sarcopenia Trial (FrOST). Forty-three sedentary community-dwelling older men (aged 73 to 91 years) with osteopenia/osteoporosis and SMI-based sarcopenia were randomly assigned to a HIT-RT exercise group (EG; n = 21) or a control group (CG; n = 22). HIT-RT provided a progressive, periodized single-set DRT on machines with high intensity, effort, and velocity twice a week, while CG maintained their lifestyle. Both groups were adequately supplemented with whey protein, vitamin D, and calcium. Primary study endpoint was integral lumbar spine (LS) BMD as determined by quantitative computed tomography. Core secondary study endpoint was SMI as determined by dual-energy X-ray absorptiometry. Additional study endpoints were BMD at the total hip and maximum isokinetic hip-/leg-extensor strength (leg press). After 12 months of exercise, LS-BMD was maintained in the EG and decreased significantly in the CG, resulting in significant between-group differences (p < 0.001; standardized mean difference [SMD] = 0.90). In parallel, SMI increased significantly in the EG and decreased significantly in the CG (p < 0.001; SMD = 1.95). Total hip BMD changes did not differ significantly between the groups (p = 0.064; SMD = 0.65), whereas changes in maximum hip-/leg-extensor strength were much more prominent (p < 0.001; SMD = 1.92) in the EG. Considering dropout (n = 2), attendance rate (95\%), and unintended side effects/injuries (n = 0), we believe our HIT-RT protocol to be feasible, attractive, and safe. In summary, we conclude that our combined low-threshold HIT-RT/protein/vitamin D/calcium intervention was feasible, safe, and effective for tackling sarcopenia and osteopenia/osteoporosis in older men with osteosarcopenia.}, language = {en} } @article{KleefeldtBoemmelBroedeetal.2019, author = {Kleefeldt, Florian and B{\"o}mmel, Heike and Broede, Britta and Thomsen, Michael and Pfeiffer, Verena and W{\"o}rsd{\"o}rfer, Philipp and Karnati, Srikanth and Wagner, Nicole and Rueckschloss, Uwe and Erg{\"u}n, S{\"u}leyman}, title = {Aging-related carcinoembryonic antigen-related cell adhesion molecule 1 signaling promotes vascular dysfunction}, series = {Aging Cell}, volume = {2019}, journal = {Aging Cell}, number = {18}, doi = {10.1111/acel.13025}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201231}, pages = {e13025}, year = {2019}, abstract = {Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF-α is CEACAM1-dependently upregulated in the aging vasculature. Vice versa, TNF-α induces CEACAM1 expression. This results in a feed-forward loop in the aging vasculature that maintains a chronic pro-inflammatory milieu. Furthermore, we demonstrate that age-associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age-dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR-2 signaling. Consequently, aging-related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.}, language = {en} } @article{OdorferWindZeller2019, author = {Odorfer, Thorsten M. and Wind, Teresa and Zeller, Daniel}, title = {Temporal discrimination thresholds and proprioceptive performance: impact of age and nerve conduction}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {1241}, issn = {1662-453X}, doi = {10.3389/fnins.2019.01241}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195648}, year = {2019}, abstract = {Background Increasing attention is payed to the contribution of somatosensory processing in motor control. In particular, temporal somatosensory discrimination has been found to be altered differentially in common movement disorders. To date, there have only been speculations as to how impaired temporal discrimination and clinical motor signs may relate to each other. Prior to disentangling this relationship, potential confounders of temporal discrimination, in particular age and peripheral nerve conduction, should be assessed, and a quantifiable measure of proprioceptive performance should be established. ObjectiveTo assess the influence of age and polyneuropathy (PNP) on somatosensory temporal discrimination threshold (STDT), temporal discrimination movement threshold (TDMT), and behavioral measures of proprioception of upper and lower limbs. Methods STDT and TDMT were assessed in 79 subjects (54 healthy, 25 with PNP; age 30-79 years). STDT was tested with surface electrodes over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpi radialis (FCR) and tibialis anterior (TA) muscle. Goniometer-based devices were used to assess limb proprioception during (i) active pointing to LED markers, (ii) active movements in response to variable visual cues, and (iii) estimation of limb position following passive movements. Pointing (or estimation) error was taken as a measure of proprioceptive performance. Results In healthy subjects, higher age was associated with higher STDT and TDMT at upper and lower extremities, while age did not correlate with proprioceptive performance. Patients with PNP showed higher STDT and TDMT values and decreased proprioceptive performance in active pointing tasks compared to matched healthy subjects. As an additional finding, there was a significant correlation between performance in active pointing tasks and temporal discrimination thresholds. Conclusion Given their notable impact on measures of temporal discrimination, age and peripheral nerve conduction need to be accounted for if STDT and TDMT are applied in patients with movement disorders. As a side observation, the correlation between measures of proprioception and temporal discrimination may prompt further studies on the presumptive link between these two domains.}, language = {en} } @article{PetruskiIvlevaKucharskaNewtonPaltaetal.2017, author = {Petruski-Ivleva, Natalia and Kucharska-Newton, Anna and Palta, Priya and Couper, David and Meyer, Katie and Graff, Misa and Haring, Bernhard and Sharrett, Richey and Heiss, Gerardo}, title = {Milk intake at midlife and cognitive decline over 20 years. The Atherosclerosis risk in communities (ARIC) study}, series = {Nutrients}, volume = {9}, journal = {Nutrients}, number = {10}, doi = {10.3390/nu9101134}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173909}, year = {2017}, abstract = {Background: Faster rates of cognitive decline are likely to result in earlier onset of cognitive impairment and dementia. d-galactose, a derivative of lactose, is used in animal studies to induce neurodegeneration. Milk is the primary source of lactose in the human diet, and its effects on cognitive decline have not been fully evaluated. Objective: Assess the association of milk intake with change in cognitive function over 20 years. Methods: A total of 13,751 participants of the Atherosclerosis Risk in Communities (ARIC) cohort completed a food frequency questionnaire and three neurocognitive evaluations from 1990 through 2013. Two single nucleotide polymorphisms (SNPs) were used to determine lactase persistence (LCT-13910 C/T for Whites and LCT-14010 G/C for Blacks). Mixed-effects models were used to study the association of milk intake with cognitive change. Multiple imputations by chained equations were used to account for attrition. Results: Milk intake greater than 1 glass/day was associated with greater decline in the global z-score over a 20-year period. The difference in decline was 0.10 (95\% CI: 0.16, 0.03) z-scores, or an additional 10\% decline, relative to the group reporting "almost never" consuming milk. Conclusions: Replication of these results is warranted in diverse populations with greater milk intake and higher variability of lactase persistence genotype.}, language = {en} } @article{Prelog2012, author = {Prelog, Martina}, title = {Differential Approaches for Vaccination from Childhood to Old Age}, series = {Gerontology}, volume = {59}, journal = {Gerontology}, number = {3}, issn = {0304-324X}, doi = {10.1159/000343475}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196602}, pages = {230-239}, year = {2012}, abstract = {Primary prevention strategies, such as vaccinations at the age extremes, in neonates and elderly individuals, demonstrate a challenge to health professionals and public health specialists. The aspects of the differentiation and maturation of the adaptive immune system, the functional implications of immunological immaturity or immunosenescence and its impact on vaccine immunogenicity and efficacy will be highlighted in this review. Several approaches have been undertaken to promote Th1 responses in neonates and to enhance immune functions in elderly, such as conjugation to carrier proteins, addition of adjuvants, concomitant vaccination with other vaccines, change in antigen concentrations or dose intervals or use of different administration routes. Also, early protection by maternal vaccination seems to be beneficial in neonates. However, it also appears necessary to think of other end points than antibody concentrations to assess vaccine efficacy in neonates or elderly, as also the cellular immune response may be impaired by the mechanisms of immaturity, underlying health conditions, immunosuppressive treatments or immunosenescence. Thus, lifespan vaccine programs should be implemented to all individuals on a population level not only to improve herd protection and to maintain protective antibody levels and immune memory, but also to cover all age groups, to protect unvaccinated elderly persons and to provide indirect protection for neonates and small infants.}, language = {en} } @article{SalvadorBurekLoehretal.2021, author = {Salvador, Ellaine and Burek, Malgorzata and L{\"o}hr, Mario and Nagai, Michiaki and Hagemann, Carsten and F{\"o}rster, Carola Y.}, title = {Senescence and associated blood-brain barrier alterations in vitro}, series = {Histochemistry and Cell Biology}, volume = {156}, journal = {Histochemistry and Cell Biology}, number = {3}, issn = {1432-119X}, doi = {10.1007/s00418-021-01992-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267435}, pages = {283-292}, year = {2021}, abstract = {Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.}, language = {en} } @article{SchlechtThienWolfetal.2021, author = {Schlecht, Anja and Thien, Adrian and Wolf, Julian and Prinz, Gabriele and Agostini, Hansj{\"u}rgen and Schlunck, G{\"u}nther and Wieghofer, Peter and Boneva, Stefaniya and Lange, Clemens}, title = {Immunosenescence in choroidal neovascularization (CNV) — Transcriptional profiling of na{\"i}ve and CNV-associated retinal myeloid cells during aging}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {24}, issn = {1422-0067}, doi = {10.3390/ijms222413318}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284342}, year = {2021}, abstract = {Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1\(^{GFP/+}\) mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.}, language = {en} } @article{TarauBerlinCurcioetal.2019, author = {Tarau, Ioana-Sandra and Berlin, Andreas and Curcio, Christine A. and Ach, Thomas}, title = {The cytoskeleton of the retinal pigment epithelium: from normal aging to age-related macular degeneration}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms20143578}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201781}, year = {2019}, abstract = {The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, adjacent to the fenestrated capillaries of the choriocapillaris. It shows strong apical (towards photoreceptors) to basal/basolateral (towards Bruch membrane) polarization. Multiple functions are bound to a complex structure of highly organized and polarized intracellular components: the cytoskeleton. A strong connection between the intracellular cytoskeleton and extracellular matrix is indispensable to maintaining the function of the RPE and thus, the photoreceptors. Impairments of these intracellular structures and the regular architecture they maintain often result in a disrupted cytoskeleton, which can be found in many retinal diseases, including age-related macular degeneration (AMD). This review article will give an overview of current knowledge on the molecules and proteins involved in cytoskeleton formation in cells, including RPE and how the cytoskeleton is affected under stress conditions — especially in AMD.}, language = {en} } @article{VeniaminovaCespuglioChernukhaetal.2020, author = {Veniaminova, Ekaterina and Cespuglio, Raymond and Chernukha, Irina and Schmitt-Boehrer, Angelika G. and Morozov, Sergey and Kalueff, Allan V. and Kuznetsova, Oxana and Anthony, Daniel C. and Lesch, Klaus-Peter and Strekalova, Tatyana}, title = {Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?}, series = {Frontiers in Neuroscience}, volume = {14}, journal = {Frontiers in Neuroscience}, issn = {1662-453X}, doi = {10.3389/fnins.2020.00024}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199813}, year = {2020}, abstract = {Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a "Western diet" (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert\(^{-/-}\): KO), heterozygous (Sert\(^{+/-}\): HET), or wild-type mice (Sert\(^{+/+}\): WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a "rescued" phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert\(^{+/-}\) mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.}, language = {en} } @phdthesis{Yuan2023, author = {Yuan, Xidi}, title = {Aging and inflammation in the peripheral nervous system}, doi = {10.25972/OPUS-23737}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237378}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Aging is known to be a risk factor for structural abnormalities and functional decline in the nervous system. Characterizing age-related changes is important to identify putative pathways to overcome deleterious effects and improve life quality for the elderly. In this study, the peripheral nervous system of 24-month-old aged C57BL/6 mice has been investigated and compared to 12-month-old adult mice. Aged mice showed pathological alterations in their peripheral nerves similar to nerve biopsies from elderly human individuals, with nerve fibers showing demyelination and axonal damage. Such changes were lacking in nerves of adult 12-month-old mice and adult, non-aged humans. Moreover, neuromuscular junctions of 24-month-old mice showed increased denervation compared to adult mice. These alterations were accompanied by elevated numbers of macrophages in the peripheral nerves of aged mice. The neuroinflammatory conditions were associated with impaired myelin integrity and with a decline of nerve conduction properties and muscle strength in aged mice. To determine the pathological impact of macrophages in the aging mice, macrophage depletion was performed in mice by oral administration of CSF-1R specific kinase (c-FMS) inhibitor PLX5622 (300 mg/kg body weight), which reduced the number of macrophages in the peripheral nerves by 70\%. The treated mice showed attenuated demyelination, less muscle denervation and preserved muscle strength. This indicates that macrophage-driven inflammation in the peripheral nerves is partially responsible for the age-related neuropathy in mice. Based on previous observations that systemic inflammation can accelerate disease progression in mouse models of neurodegenerative diseases, it was hypothesized that systemic inflammation can exacerbate the peripheral neuropathy found in aged mice. To investigate this hypothesis, aged C57BL/6 mice were intraperitoneally injected with a single dose of lipopolysaccharide (LPS; 500 μg/kg body weight) to induce systemic inflammation by mimicking bacterial infection, mostly via activation of Toll-like receptors (TLRs). Altered endoneurial macrophage activation, highlighted by Trem2 downregulation, was found in LPS injected aged mice one month after injection. This was accompanied by a so far rarely observed form of axonal perturbation, i.e., the occurrence of "dark axons" characterized by a damaged cytoskeleton and an increased overall electron density of the axoplasm. At the same time, however, LPS injection reduced demyelination and muscle denervation in aged mice. Interestingly, TREM2 deficiency in aged mice led to similar changes to LPS injection. This suggests that LPS injection likely mitigates aging-related demyelination and muscle denervation via Trem2 downregulation. Taken together, this study reveals the role of macrophage-driven inflammation as a pathogenic mediator in age-related peripheral neuropathy, and that targeting macrophages might be an option to mitigate peripheral neuropathies in aging individuals. Furthermore, this study shows that systemic inflammation may be an ambivalent modifier of age-related nerve damage, leading to a distinct type of axonal perturbation, but in addition to functionally counteracting, dampened demyelination and muscle denervation. Translationally, it is plausible to assume that tipping the balance of macrophage polarization to one direction or the other may determine the functional outcome in the aging peripheral nervous system of the elderly.}, subject = {Maus}, language = {en} } @article{ZannasArlothCarrilloRoaetal.2015, author = {Zannas, Anthony S. and Arloth, Janine and Carrillo-Roa, Tania and Iurato, Stella and R{\"o}h, Simone and Ressler, Kerry J. and Nemeroff, Charles B. and Smith, Alicia K. and Bradley, Bekh and Heim, Christine and Menke, Andreas and Lange, Jennifer F. and Br{\"u}ckl, Tanja and Ising, Marcus and Wray, Naomi R. and Erhardt, Angelika and Binder, Elisabeth B. and Mehta, Divya}, title = {Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling}, series = {Genome Biology}, volume = {16}, journal = {Genome Biology}, number = {266}, doi = {10.1186/s13059-015-0828-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149865}, year = {2015}, abstract = {Background Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. Results We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 \% (110/353) of these CpGs and transcription in 81.7 \% (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Conclusions Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.}, language = {en} } @article{ZulloFleckensteinSchleipetal.2020, author = {Zullo, Alberto and Fleckenstein, Johannes and Schleip, Robert and Hoppe, Kerstin and Wearing, Scott and Klingler, Werner}, title = {Structural and Functional Changes in the Coupling of Fascial Tissue, Skeletal Muscle, and Nerves During Aging}, series = {Frontiers in Physiology}, volume = {11}, journal = {Frontiers in Physiology}, number = {592}, issn = {1664-042X}, doi = {10.3389/fphys.2020.00592}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206890}, year = {2020}, abstract = {Aging is a one-way process associated with profound structural and functional changes in the organism. Indeed, the neuromuscular system undergoes a wide remodeling, which involves muscles, fascia, and the central and peripheral nervous systems. As a result, intrinsic features of tissues, as well as their functional and structural coupling, are affected and a decline in overall physical performance occurs. Evidence from the scientific literature demonstrates that senescence is associated with increased stiffness and reduced elasticity of fascia, as well as loss of skeletal muscle mass, strength, and regenerative potential. The interaction between muscular and fascial structures is also weakened. As for the nervous system, aging leads to motor cortex atrophy, reduced motor cortical excitability, and plasticity, thus leading to accumulation of denervated muscle fibers. As a result, the magnitude of force generated by the neuromuscular apparatus, its transmission along the myofascial chain, joint mobility, and movement coordination are impaired. In this review, we summarize the evidence about the deleterious effect of aging on skeletal muscle, fascial tissue, and the nervous system. In particular, we address the structural and functional changes occurring within and between these tissues and discuss the effect of inflammation in aging. From the clinical perspective, this article outlines promising approaches for analyzing the composition and the viscoelastic properties of skeletal muscle, such as ultrasonography and elastography, which could be applied for a better understanding of musculoskeletal modifications occurring with aging. Moreover, we describe the use of tissue manipulation techniques, such as massage, traction, mobilization as well as acupuncture, dry needling, and nerve block, to enhance fascial repair.}, language = {en} }