scholarly journals Age-dependent changes in protein incorporation into collagen-rich tissues of mice by in vivo pulsed SILAC labelling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yoanna Ariosa-Morejon ◽  
Alberto Santos ◽  
Roman Fischer ◽  
Simon Davis ◽  
Philip Charles ◽  
...  
Keyword(s):  
Skeletal Maturity ◽  
Tissue Level ◽  
Skeletal Maturation ◽  
Healthy Life ◽  
Adult Mice ◽  
Age Related ◽  
Age Dependent ◽  
Protein Incorporation ◽  
New Protein

Collagen-rich tissues have poor reparative capacity that predisposes to common age-related disorders such as osteoporosis and osteoarthritis. We used in vivo pulsed SILAC labelling to quantify new protein incorporation into cartilage, bone, and skin of mice across the healthy life course. We report dynamic turnover of the matrisome, the proteins of the extracellular matrix, in bone and cartilage during skeletal maturation, which was markedly reduced after skeletal maturity. Comparing young adult with older adult mice, new protein incorporation was reduced in all tissues. STRING clustering revealed changes in epigenetic modulators across all tissues, a decline in chondroprotective growth factors such as FGF2 and TGFβ in cartilage, and clusters indicating mitochondrial dysregulation and reduced collagen synthesis in bone. Several pathways were implicated in age-related disease. Fewer changes were observed for skin. This methodology provides dynamic protein data at a tissue level, uncovering age-related molecular changes that may predispose to disease.

scholarly journals Age-dependent changes in protein incorporation into collagen-rich tissues of mice by in vivo pulsed SILAC labelling

2021 ◽  
Author(s):  
Yoanna Ariosa-Morejon ◽  
Alberto Santos ◽  
Roman Fischer ◽  
Simon Davis ◽  
Philip Charles ◽  
...  
Keyword(s):  
Skeletal Maturity ◽  
Tissue Level ◽  
Skeletal Maturation ◽  
Adult Mice ◽  
Age Related ◽  
Protein Incorporation ◽  
Epigenetic Modulation ◽  
The Life Course ◽  
New Protein

AbstractCollagen-rich tissues have poor reparative capacity that is further impaired with age, predisposing to common age-related disorders such as osteoporosis and osteoarthritis. We used in vivo pulsed SILAC labelling to quantify new protein incorporation into cartilage, bone, skin and plasma of mice across the life course. We report highly dynamic matrisome turnover in bone and cartilage during skeletal maturation, which was markedly reduced after skeletal maturity. Comparing young adult with older adult mice, new protein incorporation was reduced in all tissues. STRING clustering revealed epigenetic modulation across all tissues, a decline in chondroprotective growth factors such as FGF2 and TGFb in cartilage, and clusters indicating mitochondrial dysregulation and reduced collagen synthesis in bone. Several of these pathways have been associated with age-related disease. Fewer changes were observed for skin and plasma. This methodology provides dynamic protein data at a tissue level, uncovering age-related molecular changes that may predispose to disease.

Abstract 1421: In Vivo Measurement of Flow-Mediated Vasodilation in Living Rats using High Resolution Ultrasound: Age-Dependent Endothelial Dysfunction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Christian Heiss ◽  
Richard E Sievers ◽  
Nicolas Amabile ◽  
Tony Y Momma ◽  
Shobha Natarajan ◽  
...  
Keyword(s):  
High Resolution ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Femoral Artery ◽  
Reactive Hyperemia ◽  
Surrogate Marker ◽  
Flow Measurements ◽  
Age Related ◽  
Age Dependent

In humans, endothelial function serves as a surrogate marker for cardiovascular health and is measured as changes in arterial diameter after temporary ischemia (flow-mediated dilation; FMD). We developed an FMD-related approach to study conduit artery vasodilation in living rats, and demonstrate a reduction in FMD in older versus younger animals consistent with age-related endothelial dysfunction. Diameter and Doppler-flow measurements were obtained from the femoral artery using high-resolution ultrasound (35 MHz). We observed dose-dependent vasodilation using both endothelium-dependent and endothelium-independent pharmacologic vasodilators (acetylcholine and nitroglycerine). Flow-dependent vasodilation was observed in response to flow increase induced both by adenosine and local saline infusion. Transient hindlimb ischemia led to reactive hyperemia with sequential flow velocity increase and femoral artery dilation, the latter of which was completely abolished by NO-synthase (NOS) inhibition with L-NMMA. To demonstrate its applicability in a model of endothelial dysfunction, we show that FMD is significantly reduced in older versus younger animals. While FMD was completely NOS-dependent in younger animals, NOS-dependent mechanisms accounted for only half of the FMD in older animals, with the remainder being blocked by charybdotoxin (CTx) and apamin suggesting contribution of endothelium-derived-hyperpolarizing-factor. Using this new integrative physiologic model to reproducibly study FMD in living rats, we show that age-dependent endothelial dysfunction is accompanied by a shift in mechanisms underlying vasodilatory endothelial function.

scholarly journals In Vivo Imaging of Cerebral Microvascular Plasticity from Birth to Death

2012 ◽  
Vol 33 (1) ◽  
pp. 146-156 ◽  
Author(s):  
Roa Harb ◽  
Christina Whiteus ◽  
Catarina Freitas ◽  
Jaime Grutzendler
Keyword(s):  
Large Scale ◽  
Time Lapse ◽  
Confocal Imaging ◽  
Adult Brain ◽  
Vessel Formation ◽  
Adult Mice ◽  
Age Related ◽  
Vascular Stability

Cerebral function and viability are critically dependent on efficient delivery of oxygen and glucose through the microvasculature. Here, we studied individual microvessels in the intact brain using high-resolution confocal imaging and long-term time-lapse two-photon microscopy across the lifetime of a mouse. In the first postnatal month, we found large-scale sprouting but to our surprise the majority of sprouts underwent pruning and only a small fraction became perfused capillaries. After the first month, microvessel formation and elimination decreased and the net number of vessels stabilized. Although vascular stability was the hallmark of the adult brain, some vessel formation and elimination continued throughout life. In young adult mice, vessel formation was markedly increased after exposure to hypoxia; however, upon return to normoxia, no vessel elimination was observed, suggesting that new vessels constitute a long-term adaptive response to metabolic challenges. This plasticity was markedly reduced in older adults and aging where hypoxia-induced angiogenesis was absent. Our study describes, for the first time in vivo patterns of cerebral microvascular remodeling throughout life. Disruption of the observed balance between baseline turnover and vascular stability may underlie a variety of developmental and age-related degenerative neurological disorders.

scholarly journals Impaired dynamics of brain precapillary sphincters and first order capillaries explains reduced neurovascular functions in aging

2021 ◽  
Author(s):  
Changsi Cai ◽  
Stefan Andreas Zambach ◽  
Soeren Grubb ◽  
Kirsten Joan Thomsen ◽  
Barbara Lykke Lind ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Reactivity ◽  
Brain Aging ◽  
Capillary Density ◽  
Nitric Oxide Synthase Inhibitor ◽  
First Order ◽  
Age Related ◽  
Age Dependent ◽  
Synthase Inhibitor

The microvascular inflow tract (MIT), i.e. penetrating arterioles, precapillary sphincters and first order capillaries, is the bottleneck for brain blood flow and energy supply. However, the exact structural and functional alterations during aging remain elusive. Using in vivo 4-dimensional (xyzt) two-photon imaging, we showed an age-dependent decrease in vaso-responsivity, which was accompanied by reduced sensitivity of MIT to pinacidil and papaverine, and to vasoconstrictors endothelin-1 and to L-NAME, a nitric oxide synthase inhibitor. Reduced responsivity was accompanied by an age-dependent decrease in capillary density close to the arterioles and by loss of pericyte processes, whereas the number of pericyte somas and the pericyte αSMA density were preserved. The age-related reduction in vascular reactivity was most pronounced at precapillary sphincters, highlighting its crucial role for capillary blood flow regulation. Mathematical modeling further revealed dysregulated but protected pressure and flow in aged mice towards vasoconstriction. Prevention of reduced responsivity of the MIT may ameliorate the blood flow decrease associated with brain aging and age-related brain frailty.

scholarly journals Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Dorota Rogińska ◽  
Miłosz P. Kawa ◽  
Ewa Pius-Sadowska ◽  
Renata Lejkowska ◽  
Karolina Łuczkowska ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Global Gene Expression ◽  
Complement Component ◽  
Oxidative Stress Marker ◽  
Age Related ◽  
Age Dependent ◽  
Autophagic Activity

The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT), electrophysiological function (ERG), and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1) alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2) significantly higher levels of antioxidant enzymes (catalase and glutathione reductase) and the antiapoptotic survivin and Mcl-1/Bak dimer, (3) lower expression of the cellular oxidative stress marker—4HNE—and decreased activity of proapoptotic caspase-3, (4) ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE) layer, and (5) significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

scholarly journals Healthy Brain Aging Modifies Microglial Calcium Signaling In Vivo

2019 ◽  
Vol 20 (3) ◽  
pp. 589 ◽  
Author(s):  
Maria Olmedillas del Moral ◽  
Nithi Asavapanumas ◽  
Néstor Uzcátegui ◽  
Olga Garaschuk
Keyword(s):  
Young Adult ◽  
Brain Aging ◽  
Critical Role ◽  
Low Grade ◽  
Middle Aged ◽  
Senescent Phenotype ◽  
Adult Mice ◽  
Age Related ◽  
Old Mice

Brain aging is characterized by a chronic, low-grade inflammatory state, promoting deficits in cognition and the development of age-related neurodegenerative diseases. Malfunction of microglia, the brain-resident immune cells, was suggested to play a critical role in neuroinflammation, but the mechanisms underlying this malfunctional phenotype remain unclear. Specifically, the age-related changes in microglial Ca2+ signaling, known to be linked to its executive functions, are not well understood. Here, using in vivo two-photon imaging, we characterize intracellular Ca2+ signaling and process extension of cortical microglia in young adult (2–4-month-old), middle-aged (9–11-month-old), and old (18–21-month-old) mice. Our data revealed a complex and nonlinear dependency of the properties of intracellular Ca2+ signals on an animal’s age. While the fraction of cells displaying spontaneous Ca2+ transients progressively increased with age, the frequencies and durations of the spontaneous Ca2+ transients followed a bell-shaped relationship, with the most frequent and largest Ca2+ transients seen in middle-aged mice. Moreover, in old mice microglial processes extending toward an ATP source moved faster but in a more disorganized manner, compared to young adult mice. Altogether, these findings identify two distinct phenotypes of aging microglia: a reactive phenotype, abundantly present in middle-aged animals, and a dysfunctional/senescent phenotype ubiquitous in old mice.

Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin

2010 ◽  
Vol 103 (05) ◽  
pp. 1085-1090 ◽  
Author(s):  
Vera Ignjatovic ◽  
Linda Johnston ◽  
Robyn Summerhayes ◽  
Geoff Lane ◽  
Noel Cranswick ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Unfractionated Heparin ◽  
Anticoagulant Activity ◽  
Venous Blood ◽  
Fold Increase ◽  
Age Related ◽  
Age Dependent ◽  
Proportional Increase ◽  
One Year

SummaryPrevious studies investigating continuous unfractionated heparin (UFH) therapy report age-related differences in UFH response in children, as measured by APTT and anti-Xa assay. This study determined the age-related response following administration of a single UFH bolus of 75–100 IU/kg in children. Venous blood samples were collected from children (n=56) at 15, 30, 45 and 120 minutes post-UFH. Anti-Xa, anti-IIa, APTT, TCT and protamine titration were performed on all samples. Age-dependent differences in the effect and concentration of UFH were identified for the anti-Xa, anti-IIa and protamine titration as-says, respectively. In addition, a trend suggesting a proportional increase in anti-Xa and anti-IIa-mediated UFH effect with age was evident. Logistic regression demonstrated an increase in protamine titration of 0.6 IU/ml for every year of age in samples collected 15 minutes post-UFH. UFH-mediated anti-IIa activity was reduced compared to anti-Xa activity across childhood, with a two-fold increase in anti-Xa to anti-IIa ratio in infants less than one year of age compared to teenagers in the setting of high UFH concentrations. This study demonstrates that the previously reported age-dependent response to UFH occurs in the context of an age-dependent serum concentration of UFH. The trend toward increased UFH serum concentration and anticoagulant activity with age may be related to short-term differences in UFH binding to coagulant and competitive plasma proteins in vivo.

Quantification of Age-Related Tissue-Level Failure Strains of Rat Femoral Cortical Bones Using an Approach Combining Macrocompressive Test and Microfinite Element Analysis

2016 ◽  
Vol 138 (4) ◽  
Author(s):  
Ruoxun Fan ◽  
He Gong ◽  
Rui Zhang ◽  
Jiazi Gao ◽  
Zhengbin Jia ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Cortical Bone ◽  
Failure Strain ◽  
Skeletal Maturity ◽  
Tissue Level ◽  
Male Rat ◽  
Bone Mechanical Properties ◽  
Age Related ◽  
Different Ages ◽  
Different Levels

Bone mechanical properties vary with age; meanwhile, a close relationship exists among bone mechanical properties at different levels. Therefore, conducting multilevel analyses for bone structures with different ages are necessary to elucidate the effects of aging on bone mechanical properties at different levels. In this study, an approach that combined microfinite element (micro-FE) analysis and macrocompressive test was established to simulate the failure of male rat femoral cortical bone. Micro-FE analyses were primarily performed for rat cortical bones with different ages to simulate their failure processes under compressive load. Tissue-level failure strains in tension and compression of these cortical bones were then back-calculated by fitting the experimental stress–strain curves. Thus, tissue-level failure strains of rat femoral cortical bones with different ages were quantified. The tissue-level failure strain exhibited a biphasic behavior with age: in the period of skeletal maturity (1–7 months of age), the failure strain gradually increased; when the rat exceeded 7 months of age, the failure strain sharply decreased. In the period of skeletal maturity, both the macro- and tissue-levels mechanical properties showed a large promotion. In the period of skeletal aging (9–15 months of age), the tissue-level mechanical properties sharply deteriorated; however, the macromechanical properties only slightly deteriorated. The age-related changes in tissue-level failure strain were revealed through the analysis of male rat femoral cortical bones with different ages, which provided a theoretical basis to understand the relationship between rat cortical bone mechanical properties at macro- and tissue-levels and decrease of bone strength with age.

scholarly journals Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids

2020 ◽  
Vol 176 (2) ◽  
pp. 460-469
Author(s):  
Pankajini Mallick ◽  
Gina Song ◽  
Alina Y Efremenko ◽  
Salil N Pendse ◽  
Moire R Creek ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Life Stage ◽  
Internal Exposure ◽  
Target Tissue ◽  
Important Conclusion ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based ◽  
Age Dependent

Abstract The assessment of potentially sensitive populations is an important application of risk assessment. To address the concern for age-related sensitivity to pyrethroid insecticides, life-stage physiologically based pharmacokinetic (PBPK) modeling supported by in vitro to in vivo extrapolation was conducted to predict age-dependent changes in target tissue exposure to 8 pyrethroids. The purpose of this age-dependent dosimetry was to calculate a Data-derived Extrapolation Factor (DDEF) to address age-related pharmacokinetic differences for pyrethroids in humans. We developed a generic human PBPK model for pyrethroids based on our previously published rat model that was developed with in vivo rat data. The results demonstrated that the age-related differences in internal exposure to pyrethroids in the brain are largely determined by the differences in metabolic capacity and in physiology for pyrethroids between children and adults. The most important conclusion from our research is that, given an identical external exposure, the internal (target tissue) concentration is equal or lower in children than in adults in response to the same level of exposure to a pyrethroid. Our results show that, based on the use of the life-stage PBPK models with 8 pyrethroids, DDEF values are essentially close to 1, resulting in a DDEF for age-related pharmacokinetic differences of 1. For risk assessment purposes, this indicates that no additional adjustment factor is necessary to account for age-related pharmacokinetic differences for these pyrethroids.

scholarly journals Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice

2020 ◽  
Author(s):  
David V.C. Brito ◽  
Kubra Gulmez Karaca ◽  
Janina Kupke ◽  
Franziska Mudlaff ◽  
Benjamin Zeuch ◽  
...  
Keyword(s):  
Young Adult ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Memory Impairments ◽  
Adult Mice ◽  
Age Related ◽  
Mouse Hippocampus ◽  
Age Dependent ◽  
And Function ◽  
Dependent Processes

AbstractAging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45γ) during aging and cognition. We report that Gadd45γ expression is increased in the hippocampus of aged humans and that Gadd45γ overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45γ overexpression in hippocampal neurons disrupted CREB signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45γ expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

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