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.

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 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 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.

scholarly journals ACCELERATED CHILDHOOD SKELETAL AGING IS PROTECTIVE OF DEVELOPMENT OF SARCOPENIA IN LATER LIFE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S608-S609
Author(s):  
Matthew J Peterson ◽  
Andrew W Froehle
Keyword(s):  
Later Life ◽  
Peak Height ◽  
Skeletal Age ◽  
Skeletal Maturation ◽  
Related Phenomenon ◽  
X Ray ◽  
Logistic Regression Models ◽  
Skeletal Aging ◽  
Age Related ◽  
The Life Course

Abstract Sarcopenia is an age-related loss of muscle mass and strength that has a multitude of adverse sequelae. Similar to other aging-related phenomenon, sarcopenia is likely the product of inputs that begin in utero and continue throughout the lifespan. We hypothesized that patterns of childhood skeletal growth predict sarcopenia status later in life. Data are from N=202 lifelong participants of the Fels Longitudinal Study (median lifetime visits=33). At the sarcopenia measure visit, participants were aged 65.8 + 10.3 years, 54% female, with body mass index of 27.5 + 4.9. Sarcopenia was defined using published sex-specific cutpoints from dual energy x-ray absorptiometry quantified appendicular lean mass/height2. Childhood skeletal age was calculated from serial hand-wrist radiographs (FELS method). Residual skeletal aging (RSA) was calculated as skeletal age minus predicted chronological age at peak height growth velocity during adolescence. RSA variance was similar in both sexes, with a range of -2 (delayed skeletal aging) to +2 years (accelerated skeletal aging). In older age, 6% of males and 22% of females exhibited sarcopenia. In multivariate logistic regression models controlling for age, self-reported physical activity, and grip strength (all measured at sarcopenia visit), accelerated RSA was protective of sarcopenia (Adjusted OR=0.58; 95% CI: 0.35-0.94). This is the first study to link childhood skeletal maturation to sarcopenia later in life. Biological pathways that explain this association likely include physiological, environmental, and genetic factors that facilitate communication between bone and muscle, and span the life course. Determining their influence is the next important step in this work.

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 Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 507
Author(s):  
Rosaria Meccariello ◽  
Stefania D’Angelo
Keyword(s):  
Oxidative Stress ◽  
Food Sources ◽  
Preventive Action ◽  
Nutritional Interventions ◽  
Beneficial Effects ◽  
Age Related ◽  
Macromolecular Damage ◽  
And Oxidative Stress

Aging and, particularly, the onset of age-related diseases are associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Recently, growing interest has emerged on the beneficial effects of plant-based diets for the prevention of chronic diseases including obesity, diabetes, and cardiovascular disease. Several studies collectively suggests that the intake of polyphenols and their major food sources may exert beneficial effects on improving insulin resistance and related diabetes risk factors, such as inflammation and oxidative stress. They are the most abundant antioxidants in the diet, and their intake has been associated with a reduced aging in humans. Polyphenolic intake has been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis, and cellular senescence, both in vitro and in vivo. In this paper, effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways. Finally, the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in polyphenolic food, such as the diets of the Blue zones, are discussed.

scholarly journals Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rahul Basu ◽  
Vinod Nair ◽  
Clayton W. Winkler ◽  
Tyson A. Woods ◽  
Iain D. C. Fraser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Virus Infection ◽  
La Crosse Virus ◽  
Brain Capillary ◽  
Adult Mice ◽  
Age Related ◽  
Capillary Endothelial Cells ◽  
The Brain

Abstract Background A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. Methods To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. Results BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. Conclusions These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease.

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