scholarly journals Dystrophin Deficiency Causes Progressive Depletion of Cardiovascular Progenitor Cells in the Heart

2021 ◽  
Vol 22 (9) ◽  
pp. 5025
Author(s):  
Sarka Jelinkova ◽  
Yvonne Sleiman ◽  
Petr Fojtík ◽  
Franck Aimond ◽  
Amanda Finan ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Speckle Tracking Echocardiography ◽  
Mdx Mice ◽  
Age Related ◽  
Age Dependent ◽  
Dystrophin Deficiency ◽  
Muscle Homeostasis ◽  
Early Recruitment

Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression of DMD-associated DCM remains unclear. In skeletal muscle, a dramatic decrease in stem cells, so-called satellite cells, has been shown in DMD patients. Whether similar dysfunction occurs with cardiac muscle cardiovascular progenitor cells (CVPCs) in DMD remains to be explored. We hypothesized that the number of CVPCs decreases in the dystrophin-deficient heart with age and disease state, contributing to DCM progression. We used the dystrophin-deficient mouse model (mdx) to investigate age-dependent CVPC properties. Using quantitative PCR, flow cytometry, speckle tracking echocardiography, and immunofluorescence, we revealed that young mdx mice exhibit elevated CVPCs. We observed a rapid age-related CVPC depletion, coinciding with the progressive onset of cardiac dysfunction. Moreover, mdx CVPCs displayed increased DNA damage, suggesting impaired cardiac muscle homeostasis. Overall, our results identify the early recruitment of CVPCs in dystrophic hearts and their fast depletion with ageing. This latter depletion may participate in the fibrosis development and the acceleration onset of the cardiomyopathy.

scholarly journals Thrombospondin-1 in maladaptive aging responses: a concept whose time has come

2020 ◽  
Vol 319 (1) ◽  
pp. C45-C63
Author(s):  
Jeffrey S. Isenberg ◽  
David D. Roberts
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Genotoxic Stress ◽  
Cell Types ◽  
Cellular Tissue ◽  
Therapeutic Agents ◽  
Age Related ◽  
Organ Systems ◽  
Age Dependent ◽  
Thrombospondin 1

Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.

scholarly journals The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis

2010 ◽  
Vol 205 (3) ◽  
pp. 201-210 ◽  
Author(s):  
Sebastio Perrini ◽  
Luigi Laviola ◽  
Marcos C Carreira ◽  
Angelo Cignarelli ◽  
Annalisa Natalicchio ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Signs And Symptoms ◽  
Well Being ◽  
Serum Levels ◽  
Normal Range ◽  
Gh Secretion ◽  
Skeletal Muscle Wasting ◽  
Age Related ◽  
Age Dependent

The widespread increase in life expectancy is accompanied by an increased prevalence of features of physical frailty. Signs and symptoms may include sarcopenia and osteopenia, reduced exercise capacity, and diminished sense of well-being. The pathogenesis of age-associated sarcopenia and osteopenia is multifactorial, and hormonal decline may be a contributing factor. Aging is associated with a progressive decrease in GH secretion, and more than 30% of elderly people have circulating IGF1 levels below the normal range found in the young. GH acts directly on target tissues, including skeletal muscle and bone among many others, but many effects are mediated indirectly by circulating (liver-derived) or locally produced IGF1. Aging is also associated with reduced insulin sensitivity which, in turn, may contribute to the impairment of IGF1 action. Recent experimental evidence suggests that besides the age-dependent decline in GH and IGF1 serum levels, the dysregulation of GH and IGF1 actions due to impairment of the post-receptor signaling machinery may contribute to the loss of muscle mass and osteopenia. This article will focus on the molecular mechanisms of impaired GH and IGF1 signaling and action in aging, and their role in the pathogenesis of sarcopenia and osteoporosis.

scholarly journals MECHANISMS OF BRAIN REJUVENATION

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S587-S587
Author(s):  
Saul Villeda
Keyword(s):  
Molecular Mechanisms ◽  
Aging Brain ◽  
Aging Effects ◽  
Effective Strategies ◽  
Mechanistic Insight ◽  
Age Related ◽  
Age Dependent ◽  
Cognitive Faculties ◽  
Insight Into ◽  
Aging Factors

Abstract A growing body of work has shown that systemic manipulations, such as heterochronic parabiosis and young blood administration, can partially reverse age-related cellular impairments and loss of cognitive faculties in the aged brain. These studies have revealed an age-dependent bi-directionality in the influence of the systemic environment indicating anti-aging factors in young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that introducing anti-aging factors or mitigating the effect of pro-aging factors may provide effective strategies to rejuvenate aging phenotypes. Despite this potential, much is unknown as to the systemic and molecular mechanisms regulating anti-aging and pro-aging effects of blood-borne factors. I will discuss work from my research group that begins to provide mechanistic insight into the systemic and molecular drivers promoting rejuvenation in the aging brain.

scholarly journals Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence

2021 ◽  
Vol 22 (6) ◽  
pp. 3107
Author(s):  
Noemi Sola-Sevilla ◽  
Ana Ricobaraza ◽  
Ruben Hernandez-Alcoceba ◽  
Maria S. Aymerich ◽  
Rosa M. Tordera ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Potential Role ◽  
Adeno Associated Virus ◽  
Age Related ◽  
Age Dependent ◽  
Molecular Effects ◽  
Samp8 Mice ◽  
The Brain

Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our results show that the specific overexpression of this isoform does not induce significant behavioral or molecular effects at short or long term in the control strain. Only a tendency towards a worsening in the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together with a significant increase in the pro-inflammatory cytokine Il-1β. These results suggest that the age-related increase of SIRT2.3 found in the brain is not responsible for induction or prevention of senescence. Nevertheless, in combination with other risk factors, it could contribute to the progression of age-related processes. Understanding the specific role of SIRT2 on aging and the underlying molecular mechanisms is essential to design new and more successful therapies for the treatment of age-related diseases.

scholarly journals Molecular Age-Related Changes in the Anterior Segment of the Eye

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Luis Fernando Hernandez-Zimbron ◽  
Rosario Gulias-Cañizo ◽  
María F. Golzarri ◽  
Blanca Elizabeth Martínez-Báez ◽  
Hugo Quiroz-Mercado ◽  
...  
Keyword(s):  
Aging Process ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Current Knowledge ◽  
Anterior Segment ◽  
Ageing Process ◽  
Degenerative Diseases ◽  
Mesh Terms ◽  
Age Related ◽  
Age Dependent

Purpose. To examine the current knowledge about the age-related processes in the anterior segment of the eye at a biological, clinical, and molecular level. Methods. We reviewed the available published literature that addresses the aging process of the anterior segment of the eye and its associated molecular and physiological events. We performed a search on PubMed, CINAHL, and Embase using the MeSH terms “eye,” “anterior segment,” and “age.” We generated searches to account for synonyms of these keywords and MESH headings as follows: (1) “Eye” AND “ageing process” OR “anterior segment ageing” and (2) “Anterior segment” AND “ageing process” OR “anterior segment” AND “molecular changes” AND “age.” Results. Among the principal causes of age-dependent alterations in the anterior segment of the eye, we found the mutation of the TGF-β gene and loss of autophagy in addition to oxidative stress, which contributes to the pathogenesis of degenerative diseases. Conclusions. In this review, we summarize the current knowledge regarding some of the molecular mechanisms related to aging in the anterior segment of the eye. We also introduce and propose potential roles of autophagy, an important mechanism responsible for maintaining homeostasis and proteostasis under stress conditions in the anterior segment during aging.

scholarly journals Regular and Moderate Exercise Counteracts the Decline of Antioxidant Protection but Not Methylglyoxal-Dependent Glycative Burden in the Ovary of Reproductively Aging Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
S. Falone ◽  
S. Jr Santini ◽  
V. Cordone ◽  
M. Grannonico ◽  
M. Cacchio ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Population Aging ◽  
Oxygen Species ◽  
Moderate Exercise ◽  
Mouse Ovary ◽  
Age Related ◽  
Age Dependent ◽  
Molecular Damage

Population aging results in urgent needs of interventions aimed at ensuring healthy senescence. Exercise often results in healthy aging, yet many molecular mechanisms underlying such effects still need to be identified. We here investigated whether the age-dependent accumulation of oxidative and methylglyoxal- (MG-) related molecular damage could be delayed by moderate exercise in the mouse ovary, an organ that first exhibits impaired function with advancing age in mammals. CD1 female mice underwent two- or four-month treadmill-based running through the transition from adult to middle age, when ovaries show signs of senescence, and markers of protection against reactive oxygen species (ROS) and MG were measured. The long-term exercise reduced the protein oxidative damage in the ovaries (P<0.01), and this was linked to the preservation of the glutathione peroxidase protection against ROS (P<0.001), as well as to the increased glutathione availability (P<0.001). Conversely, even though the age-related deactivation of the MG-targeting systems was partially prevented by the long-term running programme (P<0.001), exercised mice were not protected from the age-dependent glycative burden. In summary, lately initiated regular and moderate exercise limited some changes occurring in the ovaries of middle-aged mice, and this might help to develop nonpharmacological cointerventions to reduce the vulnerability of mammalian ovaries towards redox dysfunctions.

scholarly journals Noncanonical Wnt5a signaling regulates tendon stem/progenitor cells senescence

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Minhao Chen ◽  
Yingjuan Li ◽  
Longfei Xiao ◽  
Guangchun Dai ◽  
Panpan Lu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Qrt Pcr ◽  
Age Related ◽  
Structural And Functional Properties ◽  
Stat Signaling

Abstract Background The structural and functional properties of tendon decline with age, and these changes contribute to tendon disorder. Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair, regeneration and homeostasis maintaining. Although studies have demonstrated that tendon aging is closely associated with the altered TSPCs function on senescence, the cellular and molecular mechanisms of TSPCs senescence remain largely unknown. This study was designed to investigate the role of Wnt5a in TSPCs senescence. Methods TSPCs were isolated from 2-month-old and 20-month-old male C57BL/6 mice. The expression of Wnt5a was determined by RNA sequencing, qRT-PCR and western blotting. TSPCs were then treated with Wnt5a shRNA or recombinant Wnt5a or AG490 or IFN-γ or Ror2-siRNA. Western blotting, β-gal staining, qRT-PCR, immunofluorescence staining and cell cycle analysis were used for confirming the role of Wnt5a in TSPCs senescence. Results We found a canonical to noncanonical Wnt signaling shift due to enhanced expression of Wnt5a in aged TSPCs. Functionally, we demonstrated that inhibition of Wnt5a attenuated TSPCs senescence, age-related cell polarity and the senescence-associated secretory phenotype (SASP) expression in aged TSPCs. Mechanistically, the JAK–STAT signaling pathway was activated in aged TSPCs, while Wnt5a knockdown inhibited the JAK–STAT signaling pathway, suggesting that Wnt5a modulates TSPCs senescence via JAK–STAT signaling pathway. Moreover, knockdown of Ror2 inhibited Wnt5a-induced activation of the JAK–STAT signaling pathway, which indicates that Wnt5a potentiates JAK–STAT signaling pathway through Ror2, and Ror2 acts as the functional receptor of Wnt5a in TSPCs senescence. Conclusion Our results demonstrate a critical role of noncanonical Wnt5a signaling in TSPCs senescence, and Wnt5a could be an attractive therapeutic target for antagonizing tendon aging.

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.

scholarly journals Long Noncoding Competing Endogenous RNA Networks in Age-Associated Cardiovascular Diseases

2019 ◽  
Vol 20 (12) ◽  
pp. 3079 ◽  
Author(s):  
Simona Greco ◽  
Carlo Gaetano ◽  
Fabio Martelli
Keyword(s):  
Cardiovascular Diseases ◽  
Control Systems ◽  
Molecular Mechanisms ◽  
Functional Decline ◽  
Physiological Mechanisms ◽  
Age Related ◽  
Micro Rnas ◽  
Age Dependent ◽  
Competing Endogenous Rnas ◽  
Novel Therapeutic Strategies

Cardiovascular diseases (CVDs) are the most serious health problem in the world, displaying high rates of morbidity and mortality. One of the main risk factors for CVDs is age. Indeed, several mechanisms are at play during aging, determining the functional decline of the cardiovascular system. Aging cells and tissues are characterized by diminished autophagy, causing the accumulation of damaged proteins and mitochondria, as well as by increased levels of oxidative stress, apoptosis, senescence and inflammation. These processes can induce a rapid deterioration of cellular quality-control systems. However, the molecular mechanisms of age-associated CVDs are only partially known, hampering the development of novel therapeutic strategies. Evidence has emerged indicating that noncoding RNAs (ncRNAs), such as long ncRNAs (lncRNAs) and micro RNAs (miRNAs), are implicated in most patho-physiological mechanisms. Specifically, lncRNAs can bind miRNAs and act as competing endogenous-RNAs (ceRNAs), therefore modulating the levels of the mRNAs targeted by the sponged miRNA. These complex lncRNA/miRNA/mRNA networks, by regulating autophagy, apoptosis, necrosis, senescence and inflammation, play a crucial role in the development of age-dependent CVDs. In this review, the emerging knowledge on lncRNA/miRNA/mRNA networks will be summarized and the way in which they influence age-related CVDs development will be discussed.

scholarly journals Reprogramming Müller Glia to Regenerate Retinal Neurons

2020 ◽  
Vol 6 (1) ◽  
pp. 171-193 ◽  
Author(s):  
Manuela Lahne ◽  
Mikiko Nagashima ◽  
David R. Hyde ◽  
Peter F. Hitchcock
Keyword(s):  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Current Knowledge ◽  
Cellular Reprogramming ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Neurons ◽  
Age Related

In humans, various genetic defects or age-related diseases, such as diabetic retinopathies, glaucoma, and macular degeneration, cause the death of retinal neurons and profound vision loss. One approach to treating these diseases is to utilize stem and progenitor cells to replace neurons in situ, with the expectation that new neurons will create new synaptic circuits or integrate into existing ones. Reprogramming non-neuronal cells in vivo into stem or progenitor cells is one strategy for replacing lost neurons. Zebrafish have become a valuable model for investigating cellular reprogramming and retinal regeneration. This review summarizes our current knowledge regarding spontaneous reprogramming of Müller glia in zebrafish and compares this knowledge to research efforts directed toward reprogramming Müller glia in mammals. Intensive research using these animal models has revealed shared molecular mechanisms that make Müller glia attractive targets for cellular reprogramming and highlighted the potential for curing degenerative retinal diseases from intrinsic cellular sources.

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