scholarly journals Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2772
Author(s):  
Claudio Pinto ◽  
Elisabetta Ninfole ◽  
Antonio Benedetti ◽  
Marco Marzioni ◽  
Luca Maroni
Keyword(s):  
Liver Damage ◽  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Cell Damage ◽  
Degradation Process ◽  
Compensatory Mechanism ◽  
Age Related ◽  
Cholestatic Diseases ◽  
Stimulation Of

Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

scholarly journals Advances in the Role of Leucine-Sensing in the Regulation of Protein Synthesis in Aging Skeletal Muscle

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan Zhao ◽  
Jason Cholewa ◽  
Huayu Shang ◽  
Yueqin Yang ◽  
Xiaomin Ding ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Therapeutic Potential ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Trna Synthetase ◽  
Limiting Factor ◽  
Anabolic Resistance ◽  
Age Related

Skeletal muscle anabolic resistance (i.e., the decrease in muscle protein synthesis (MPS) in response to anabolic stimuli such as amino acids and exercise) has been identified as a major cause of age-related sarcopenia, to which blunted nutrition-sensing contributes. In recent years, it has been suggested that a leucine sensor may function as a rate-limiting factor in skeletal MPS via small-molecule GTPase. Leucine-sensing and response may therefore have important therapeutic potential in the steady regulation of protein metabolism in aging skeletal muscle. This paper systematically summarizes the three critical processes involved in the leucine-sensing and response process: (1) How the coincidence detector mammalian target of rapamycin complex 1 localizes on the surface of lysosome and how its crucial upstream regulators Rheb and RagB/RagD interact to modulate the leucine response; (2) how complexes such as Ragulator, GATOR, FLCN, and TSC control the nucleotide loading state of Rheb and RagB/RagD to modulate their functional activity; and (3) how the identified leucine sensor leucyl-tRNA synthetase (LARS) and stress response protein 2 (Sestrin2) participate in the leucine-sensing process and the activation of RagB/RagD. Finally, we discuss the potential mechanistic role of exercise and its interactions with leucine-sensing and anabolic responses.

scholarly journals Polyphenol Stilbenes: Molecular Mechanisms of Defence against Oxidative Stress and Aging-Related Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-24 ◽  
Author(s):  
Mika Reinisalo ◽  
Anna Kårlund ◽  
Ali Koskela ◽  
Kai Kaarniranta ◽  
Reijo O. Karjalainen
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Damage ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Age Related ◽  
Cellular Defence ◽  
The Impact ◽  
Stilbene Compounds

Numerous studies have highlighted the key roles of oxidative stress and inflammation in aging-related diseases such as obesity, type 2 diabetes, age-related macular degeneration (AMD), and Alzheimer’s disease (AD). In aging cells, the natural antioxidant capacity decreases and the overall efficiency of reparative systems against cell damage becomes impaired. There is convincing data that stilbene compounds, a diverse group of natural defence phenolics, abundant in grapes, berries, and conifer bark waste, may confer a protective effect against aging-related diseases. This review highlights recent data helping to clarify the molecular mechanisms involved in the stilbene-mediated protection against oxidative stress. The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1/p62 protein in Nrf2/Keap1 signaling and autophagy will be summarized. The therapeutic potential of stilbene compounds against the most common aging-related diseases is discussed.

scholarly journals Recent progress in research on molecular mechanisms of autophagy in the heart

2015 ◽  
Vol 308 (4) ◽  
pp. H259-H268 ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yun Chen ◽  
Mitsuaki Isobe ◽  
Åsa B. Gustafsson ◽  
Richard N. Kitsis ◽  
...  
Keyword(s):  
Heart Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Degradation Process ◽  
Structure And Function ◽  
Cellular Functions ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Cellular Dysfunction

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.

scholarly journals Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 694
Author(s):  
Georgios Konstantinidis ◽  
Nektarios Tavernarakis
Keyword(s):  
Caenorhabditis Elegans ◽  
Degradation Process ◽  
Pathogen Invasion ◽  
Age Related ◽  
Distinct Cell ◽  
Evolutionarily Conserved ◽  
Subsequent Degradation ◽  
Membrane Organelle ◽  
Neuronal Autophagy

Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane organelle referred to as the autophagosome with subsequent degradation of its contents upon delivery to lysosomes. Autophagy plays critical roles in development, maintenance and survival of distinct cell populations including neurons. Consequently, age-dependent decline in autophagy predisposes animals for age-related diseases including neurodegeneration and compromises healthspan and longevity. In this review, we summarize recent advances in our understanding of the role of neuronal autophagy in ageing, focusing on studies in the nematode Caenorhabditis elegans.

scholarly journals Role of Prohibitins in Aging and Therapeutic Potential Against Age-Related Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Misa Belser ◽  
David W. Walker
Keyword(s):  
Oxidative Phosphorylation ◽  
Therapeutic Potential ◽  
Mitochondrial Homeostasis ◽  
Organismal Biology ◽  
Mitochondrial Inner Membrane ◽  
Health Decline ◽  
Age Related ◽  
Attractive Therapeutic Target ◽  
Lines Of Evidence

A decline in mitochondrial function has long been associated with age-related health decline. Several lines of evidence suggest that interventions that stimulate mitochondrial autophagy (mitophagy) can slow aging and prolong healthy lifespan. Prohibitins (PHB1 and PHB2) assemble at the mitochondrial inner membrane and are critical for mitochondrial homeostasis. In addition, prohibitins (PHBs) have diverse roles in cell and organismal biology. Here, we will discuss the role of PHBs in mitophagy, oxidative phosphorylation, cellular senescence, and apoptosis. We will also discuss the role of PHBs in modulating lifespan. In addition, we will review the links between PHBs and diseases of aging. Finally, we will discuss the emerging concept that PHBs may represent an attractive therapeutic target to counteract aging and age-onset disease.

scholarly journals Synuclein Deficiency Results in Age-Related Respiratory and Cardiovascular Dysfunctions in Mice

2020 ◽  
Vol 10 (9) ◽  
pp. 583
Author(s):  
Patrick S. Hosford ◽  
Natalia Ninkina ◽  
Vladimir L. Buchman ◽  
Jeffrey C. Smith ◽  
Nephtali Marina ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Physiological Role ◽  
Normal Function ◽  
Whole Body ◽  
Cardiovascular Reflexes ◽  
Long Term Effects ◽  
Gene Encoding ◽  
Age Related

Synuclein (α, β, and γ) proteins are highly expressed in presynaptic terminals, and significant data exist supporting their role in regulating neurotransmitter release. Targeting the gene encoding α-synuclein is the basis of many animal models of Parkinson’s disease (PD). However, the physiological role of this family of proteins in not well understood and could be especially relevant as interfering with accumulation of α-synuclein level has therapeutic potential in limiting PD progression. The long-term effects of their removal are unknown and given the complex pathophysiology of PD, could exacerbate other clinical features of the disease, for example dysautonomia. In the present study, we sought to characterize the autonomic phenotypes of mice lacking all synucleins (α, β, and γ; αβγ−/−) in order to better understand the role of synuclein-family proteins in autonomic function. We probed respiratory and cardiovascular reflexes in conscious and anesthetized, young (4 months) and aged (18–20 months) αβγ−/− male mice. Aged mice displayed impaired respiratory responses to both hypoxia and hypercapnia when breathing activities were recorded in conscious animals using whole-body plethysmography. These animals were also found to be hypertensive from conscious blood pressure recordings, to have reduced pressor baroreflex gain under anesthesia, and showed reduced termination of both pressor and depressor reflexes. The present data demonstrate the importance of synuclein in the normal function of respiratory and cardiovascular reflexes during aging.

scholarly journals Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review

Gerontology ◽  
2016 ◽  
Vol 62 (5) ◽  
pp. 513-518 ◽  
Author(s):  
Michael C. Velarde ◽  
Marco Demaria
Keyword(s):  
Growth Factors ◽  
Targeted Therapies ◽  
Therapeutic Strategy ◽  
Functional Decline ◽  
Skin Aging ◽  
Negative Effects ◽  
Age Related ◽  
Secretory Phenotype ◽  
Excessive Accumulation

Senescent cells are induced by a wide variety of stimuli. They accumulate in several tissues during aging, including the skin. Senescent cells secrete proinflammatory cytokines, chemokines, growth factors, and proteases, a phenomenon called senescence-associated secretory phenotype (SASP), which are thought to contribute to the functional decline of the skin as a consequence of aging. Due to the potential negative effects of the SASP in aged organisms, drugs that selectively target senescent cells represent an intriguing therapeutic strategy to delay aging and age-related diseases. Here, we review studies on the role of senescent cells in the skin, with particular emphasis on the age-related mechanisms and phenotypes associated with excessive accumulation of cellular senescence. We discuss the aberrant behavior of senescent cells in aging and how the different signaling pathways associated with survival and secretion of senescent cells can be engaged for the development of targeted therapies.

scholarly journals Prospects for using agonists and antagonists of P2 receptors in clinical ophthalmology

2012 ◽  
Vol 93 (3) ◽  
pp. 508-512 ◽  
Author(s):  
A P Ziganshina ◽  
B A Ziganshin ◽  
A N Samoilov ◽  
A U Ziganshin
Keyword(s):  
P2 Receptors ◽  
Point Of View ◽  
Physiological Processes ◽  
Age Related ◽  
Corneal Wound ◽  
Clinical Point ◽  
Fluid Production ◽  
Neuronal Transmission ◽  
Stimulation Of

This literature review focuses on the role of purinergic P2-receptors in the physiology and pathophysiology of the eye, as well as on the possibilities of pharmacologic stimulation of these receptors. The most important studies from the clinical point of view on the involvement of purinergic neuronal transmission in the physiological processes have been analyzed, ranging from normal embryogenesis to cell apoptosis in age-related degenerative diseases of the eye. Data on the effect of agonists and antagonists of P2 receptors on corneal wound healing, lacrimal fluid production, regulation of intraocular pressure, neurotransmission, proliferation of glial tissue in the retina has been presented along with data on the possibilities of modulating these processes by using potential drugs acting via P2 receptors.

Role of genetic variability in systems of receptor-mediated and enzymatic defence against glycation in the long-term consequences of diabetes mellitus

2003 ◽  
Vol 31 (6) ◽  
pp. 1364-1366 ◽  
Author(s):  
K. Kaňková
Keyword(s):  
Diabetes Mellitus ◽  
Therapeutic Strategy ◽  
Cell Damage ◽  
Late Complications ◽  
Individual Risk ◽  
Intermediate Phenotypes ◽  
Carbohydrate And Lipid Metabolism ◽  
Chronic Hyperglycaemia

Diabetes mellitus is the most common metabolic disease, and has late complications that are due to chronic hyperglycaemia. Altered carbohydrate and lipid metabolism together with impaired detoxification of carbonyl substrates and impaired trapping of oxygen radicals are responsible for cell damage in diabetes. Variable functional capacity of detoxifying systems could contribute to differing susceptibility to the development of complications. Identification of genetic variants responsible for modulating relevant intermediate phenotypes in diabetics could help to define individual risk profiles and to modify therapeutic strategy accordingly.

scholarly journals Selective Retina Therapy and Thermal Stimulation of the Retina: Different Regenerative Properties - Implications for AMD Therapy

2020 ◽  
Author(s):  
Elisabeth Richert ◽  
Julia Papenkort ◽  
Claus von der Burchard ◽  
Alexa Klettner ◽  
Philipp Arnold ◽  
...  
Keyword(s):  
Cell Death ◽  
Laser Treatment ◽  
Cell Damage ◽  
Single Cells ◽  
Thermal Stimulation ◽  
Age Related Macular Degeneration ◽  
Therapeutic Effects ◽  
Selective Retina Therapy ◽  
Age Related ◽  
Stimulation Of

Abstract BackgroundSelective Retina Therapy (SRT) and Thermal Stimulation of the Retina (TSR) have shown therapeutic effects on Age-related Macular Degeneration (AMD) in mice. We investigate the differences between both laser modalities concerning RPE regeneration. MethodsFor PCR array, 6 eyes of apolipoprotein E and nuclear factor erythroid-derived 2- like 2 knock out mice respectively were treated by neuroretina-sparing TSR or SRT. Untreated litter mates were controls. Eyes were enucleated either 1 or 7 days after laser treatment. For morphological analysis, porcine RPE/choroid organ cultures underwent the same laser treatment and were examined by calcein vitality staining 1 h and 1, 3 or 5 days after irradiation. ResultsTSR did not induce the expression of cell-mediators connected to cell death. SRT induced necrosis associated cytokines as well as inflammation 1 but not 7 days after treatment. Morphologically, 1 hour after TSR, there was no cell damage. One and 3 days after TSR, dense chromatin and cell destruction of single cells was seen. Five days after TSR, there were signs of migration and proliferation. In contrast, one hour after SRT a defined necrotic area within the laser spot was seen. This lesion was closed over days by migration and proliferation of adjacent cells. ConclusionsSRT induces RPE cell death, followed by regeneration within a few days, accompanied by necrosis induced inflammation, RPE proliferation and migration. TSR does not induce immediate RPE cell death; however, migration and mitosis can be seen a few days after laser irradiation, not accompanied by necrosis-associated inflammation.

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