Collagenase‐resistant collagen promotes mouse aging and vascular cell senescence

Vafaie, Faran; Yin, Hao; O’Neil, Caroline; Zhang, Nong; Watson, Alanna; Arpino, John‐Michael; Chu, Michael; Holdsworth, David W.; Gros, Robert; Pickering, J. Geoffrey

doi:10.1111/acel.12155

Cited by 62 publications

(51 citation statements)

References 45 publications

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“…2E, blue stain, and fig. S1E), precluded collagen-induced vascular senescence (37). Notably, middle-aged wild-type lungs were abundant in senescent markers, with increased p53 and p21 cip , decreased Rb, and no change in p16 INK4A , compared to younger controls (fig.…”

Section: Resultsmentioning

confidence: 99%

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

et al. 2017

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Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue. In human endothelial cells, TSP1 promoted senescence and attenuated cell cycle progression and proliferation. At the molecular level, TSP1 increased Nox1-dependent generation of reactive oxygen species (ROS), leading to the increased abundance of the transcription factor p53. p53 mediated a DNA damage response that led to senescence through Rb and p21cip, both of which inhibit cell cycle progression. Nox1 inhibition blocked the ability of TSP1 to increase p53 nuclear localization and p21cip abundance and its ability to promote senescence. Mice lacking TSP1 showed decreases in ROS production, p21cip expression, p53 activity, and aging-induced senescence. Conversely, lung tissue from aging humans displayed increases in the abundance of vascular TSP1, Nox1, p53, and p21cip. Finally, genetic ablation or pharmacological blockade of Nox1 in human endothelial cells attenuated TSP1-mediated ROS generation, restored cell cycle progression, and protected against senescence. Together, our results provide insights into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence and suggest potential targets for controlling the aging process at the molecular level.

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Section: Resultsmentioning

confidence: 99%

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

et al. 2017

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“…b; Vafaie et al . ). Each ring was mounted isometrically onto two parallel stainless steel wires, one connected to a micrometer for fine distance adjustments and the other connected to a force transducer (FT03; Grass Instruments, Warwick, RI, USA) attached to a digital display (P11T; Grass Instruments).…”

Section: Methodsmentioning

confidence: 97%

Low birth weight followed by postnatal over‐nutrition in the guinea pig exposes a predominant player in the development of vascular dysfunction

Thompson

Sarr

Piorkowska

et al. 2014

The Journal of Physiology

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Key pointsr Suboptimal intrauterine conditions and consequent intrauterine growth reduction (IUGR), resulting in low birth weight (LBW), increase the risk for hypertension and cardiovascular disease in adulthood.r LBW offspring who experience an accelerated growth in childhood have a higher risk of cardiovascular disease than those who grow more slowly, suggesting that the postnatal environment interacts with programmed deficits in organ function to influence disease risk.r We show here that arterial stiffening in LBW guinea pig offspring is exacerbated with postnatal feeding of a Western diet, suggesting that IUGR confers heightened vascular susceptibility to postnatal risk factors and thus may contribute to an individual's total risk score.r Our results also demonstrate that the independent effect of the intrauterine environment on vascular function in young adult guinea pigs is greater than the effect of a postnatal Western diet, thus highlighting the importance of prenatal factors on long-term vascular health.Abstract The association between intrauterine growth restriction (IUGR) and hypertension is well established, yet the interaction between IUGR and other pathogenic contributors remains ill-defined. This study examined the independent and interactive effects of fetal growth reduction resulting in low birth weight (LBW), and postnatal Western diet (WD) on vascular function. Growth reduction was induced in pregnant guinea pigs by uterine artery ablation. LBW and normal birth weight (NBW) offspring were randomly assigned to a control diet (CD) or a WD. In young adulthood, length-tension curves were generated in aortic rings and responses to methacholine (MCh) were evaluated in the carotid and aorta using wire myography. Relative to NBW/CD, aortae of NBW/WD offspring were stiffer, as determined by a leftward shift in the length-tension curve, yet the shift in the LBW/CD curve was considerably greater. Aortic stiffening was most severe in LBW/WD (slope: NBW/CD, 1.97 ± 0.04; NBW/WD, 2.16 ± 0.04; LBW/CD, 2.28 ± 0.05; LBW/WD, 2.34 ± 0.07). Maximal responses (E max ) to MCh were significantly blunted in the aorta of LBW/CD vs. NBW/CD (P < 0.05) and in LBW/WD vs. NBW/WD offspring (P < 0.05); but WD alone had no influence on MCh responses. E max values for carotid responses to MCh were reduced in LBW/CD vs. NBW/CD (P < 0.05). Thus, aortic stiffening was influenced more by LBW than by a postnatal WD and the most severe stiffening was observed in LBW/WD offspring. In contrast, blunted endothelial responses in LBW/CD offspring were not exacerbated by WD. IUGR may have a greater independent impact on vascular function than a postnatal WD.

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“…We might expect that mice genetically engineered to express modified collagen COL1A1 r/r that cannot be cleaved by MMPs, would not show age-depended ECM degradation, and would live longer. However, collagen COL1A1 r/r mice showed accelerated aging, short lifespan, and cellular senescence [12], suggesting that blocking of ECM turnover is also detrimental. This points toward a balanced ECM turnover being important to maintain health during aging.…”

Section: Progressive Decline In Ecm Turnover and Dynamics During Agingmentioning

confidence: 99%

The Matrisome during Aging and Longevity: A Systems-Level Approach toward Defining Matreotypes Promoting Healthy Aging

Ewald¹

2019

Gerontology

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Accumulation of damage is generally considered the cause of aging. Interventions that delay aging mobilize mechanisms that protect and repair cellular components. Consequently, research has been focused on studying the protective and homeostatic mechanisms within cells. However, in humans and other multicellular organisms, cells are surrounded by extracellular matrices (ECMs), which are important for tissue structure, function, and intercellular communication. During aging, components of the ECM become damaged through fragmentation, glycation, crosslinking, and accumulation of protein aggregation, all of which contribute to age-related pathologies. Interestingly, placing senescent cells into a young ECM rejuvenates them. Furthermore, we found that many longevity-assurances pathways reactivate de novo synthesis of ECM proteins during aging. This raises the question of what constitutes a young ECM to reverse aging or maintain health? In order to make inroads to answering this question, I suggest a systems-level approach of quantifying the matrisome or ECM compositions reflecting health, pathology, or phenotype and propose a novel term, the "matreotype," to describe this. The matreotype is defined as the composition and modification of ECM or matrisome proteins associated with or caused by a phenotype, such as longevity, or a distinct and acute physiological state, as observed during aging or disease. Every cell type produces its unique ECM. Intriguingly, cancer-cell types can even be identified based on their unique ECM composition. Thus, the matreotype reflects cellular identity and physiological status. Defined matreotypes could be used as biomarkers or prognostic factors for disease or health status during aging with potential relevance for personalized medicine. Treatment with biologics that alter ECM-to-cell mechanotransduction might be a strategy to reverse age-associated pathologies. An understanding of how to reverse from an old to a young matreotype might point toward novel strategies to rejuvenate cells and help maintain tissue homeostasis to promote health during aging.

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Collagenase‐resistant collagen promotes mouse aging and vascular cell senescence

Cited by 62 publications

References 45 publications

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

Low birth weight followed by postnatal over‐nutrition in the guinea pig exposes a predominant player in the development of vascular dysfunction

The Matrisome during Aging and Longevity: A Systems-Level Approach toward Defining Matreotypes Promoting Healthy Aging

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